Updated on 2022/03/16

写真a

 
SUZUKI Hiroshi
 
Organization
Graduate School of Medicine Center for Neural Disease and Cancer Division Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Professor

Degree 1

  1. Ph.D. (Medical Science) ( 2010.3   The University of Tokyo ) 

Research Interests 6

  1. 相分離

  2. がん

  3. 転写

  4. エンハンサー(スーパーエンハンサー)

  5. ゲノム

  6. RNA

Research Areas 4

  1. Life Science / Pathological biochemistry  / 分子腫瘍学

  2. Life Science / Molecular biology

  3. Life Science / Genome biology

  4. Life Science / Tumor biology

Research History 12

  1. Nagoya University Graduate School of Medicine   Center for Neurological Diseases and Cancer   Professor

    2020.5

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    Country:Japan

  2. Nagoya University   Professor

    2020.5

  3. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology   Research Scientist

    2019.6 - 2020.4

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    Country:United States

  4. Massachusetts Institute of Technology   Koch Institute for Integrative Cancer Research   Research Scientist

    2019.6 - 2020.4

  5. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology   Visiting Scientist

    2014.4 - 2019.3

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    Country:United States

  6. Massachusetts Institute of Technology   Koch Institute for Integrative Cancer Research   Visiting Scientist

    2014.4 - 2019.3

  7. Graduate School of Medicine, The University of Tokyo   Department of Molecular Pathology   Designated assistant professor

    2010.4 - 2014.3

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    Country:Japan

  8. Graduate School of Medicine, The University of Tokyo   Department of Molecular Pathology   Designated assistant professor

    2010.4 - 2014.3

  9. Research Fellowship for Young Scientists, Japan Society for the Promotion of Science

    2008.5 - 2010.3

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    Country:Japan

  10. Japan Society for Promotion of Science   Research Fellowship for Young Scientists

    2008.5 - 2010.3

  11. The University of Tokyo Hospital   Senior residency (Hematology and Oncology)

    2006.3 - 2007.3

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    Country:Japan

  12. The University of Tokyo Hospital   Residency

    2004.4 - 2006.3

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    Country:Japan

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Education 4

  1. The University of Tokyo   Graduate School of Medicine

    2007.4 - 2010.3

  2. The University of Tokyo   Graduate School, Division of Medical Sciences

    2007.4 - 2010.3

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    Country: Japan

  3. The University of Tokyo   Faculty of Medicine

    1998.4 - 2004.3

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    Country: Japan

  4. The University of Tokyo   Faculty of Medicine

    - 2004.3

Professional Memberships 6

  1. The Japanese Cancer Association

  2. The Japanese Society of Hematology

  3. The RNA Society of Japan

  4. The Japanese Association for Molecular Target Therapy of Cancer

  5. The Molecular Biology Society of Japan

  6. The Japanese Biochemical Society

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Awards 10

  1. The Young Scientists’ Prize, the Ministry of Education, Culture, Sports, Science, and Technology of Japan

    2016  

  2. Japanese Biochemical Society Young Investigator Award

    2014  

  3. Incitement Award of the Japanese Cancer Association

    2013  

  4. Inoue Research Award for Young Scientists

    2013  

  5. The postar award, The University of Tokyo, 5th global COE retreat

    2012  

  6. The postar award, The 2nd International Symposium by JSPS Core-to-Core Program “Cooperative International Framework in TGF-β Family Signaling”

    2012  

  7. The University of Tokyo President's Award

    2010  

  8. The postar award, The University of Tokyo, 2nd global COE retreat

    2009  

  9. Excellent Presentation Award, The Annual Meeting of the Japanese Biochemical Society

    2009  

  10. Excellent Presentation Award, Cancer Research Workshop

    2009  

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Papers 64

  1. Biomolecular condensates in cancer biology. International journal

    Hiroshi I Suzuki, Koh Onimaru

    Cancer science   Vol. 113 ( 2 ) page: 382 - 391   2022.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    Understanding the characteristics of cancer cells is essential for the development of improved diagnosis and therapeutics. From a gene regulation perspective, the super-enhancer concept has been introduced to systematically understand the molecular mechanisms underlying the identities of various cell types and has been extended to the analysis of cancer cells and cancer genome alterations. In addition, several characteristic features of super-enhancers have led to the recognition of the link between gene regulation and biomolecular condensates, which is often mediated by liquid-liquid phase separation. Several lines of evidence have suggested molecular and biophysical principles and their alterations in cancer cells, which are particularly associated with gene regulation and cell signaling (" transcriptional" and "signaling" condensates). These findings collectively suggest that the modification of biomolecular condensates represents an important mechanism by which cancer cells acquire various cancer hallmark traits and establish functional innovation for cancer initiation and progression. The condensate model also provides the molecular basis of the vulnerability of cancer cells to transcriptional perturbation and further suggests the possibility of therapeutic targeting of condensates. This review summarizes recent findings regarding the relationships between super-enhancers and biomolecular condensate models, multiple scenarios of condensate alterations in cancers, and the potential of the condensate model for therapeutic development.

    DOI: 10.1111/cas.15232

    PubMed

  2. Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function. International journal

    Koichi Ogami, Hiroshi I Suzuki

    International journal of molecular sciences   Vol. 22 ( 24 )   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    The genome is pervasively transcribed across various species, yielding numerous non-coding RNAs. As a counterbalance for pervasive transcription, various organisms have a nuclear RNA exosome complex, whose structure is well conserved between yeast and mammalian cells. The RNA exosome not only regulates the processing of stable RNA species, such as rRNAs, tRNAs, small nucleolar RNAs, and small nuclear RNAs, but also plays a central role in RNA surveillance by degrading many unstable RNAs and misprocessed pre-mRNAs. In addition, associated cofactors of RNA exosome direct the exosome to distinct classes of RNA substrates, suggesting divergent and/or multi-layer control of RNA quality in the cell. While the RNA exosome is essential for cell viability and influences various cellular processes, mutations and alterations in the RNA exosome components are linked to the collection of rare diseases and various diseases including cancer, respectively. The present review summarizes the relationships between pervasive transcription and RNA exosome, including evolutionary crosstalk, mechanisms of RNA exosome-mediated RNA surveillance, and physiopathological effects of perturbation of RNA exosome.

    DOI: 10.3390/ijms222413401

    PubMed

  3. MCPIP1 reduces HBV-RNA by targeting its epsilon structure. International journal

    Yingfang Li, Lusheng Que, Kento Fukano, Miki Koura, Kouichi Kitamura, Xin Zheng, Takanobu Kato, Hussein Hassan Aly, Koichi Watashi, Senko Tsukuda, Hideki Aizaki, Noriyuki Watanabe, Yuko Sato, Tadaki Suzuki, Hiroshi I Suzuki, Kazuyoshi Hosomichi, Makoto Kurachi, Kousho Wakae, Masamichi Muramatsu

    Scientific reports   Vol. 10 ( 1 ) page: 20763 - 20763   2020.11

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    Language:English   Publishing type:Research paper (scientific journal)  

    Hepatitis B virus (HBV) is the major causative factor of chronic viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. We previously demonstrated that a proinflammatory cytokine IL-1β reduced the level of HBV RNA. However, the mechanism underlying IL-1β-mediated viral RNA reduction remains incompletely understood. In this study, we report that immune regulator Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) can reduce HBV RNA in hepatocytes. MCPIP1 expression level was higher in the liver tissue of HBV-infected patients and mice. Overexpression of MCPIP1 decreased HBV RNA, whereas ablating MCPIP1 in vitro enhanced HBV production. The domains responsible for RNase activity or oligomerization, were required for MCPIP1-mediated viral RNA reduction. The epsilon structure of HBV RNA was important for its antiviral activity and cleaved by MCPIP1 in the cell-free system. Lastly, knocking out MCPIP1 attenuated the anti-HBV effect of IL-1β, suggesting that MCPIP1 is required for IL-1β-mediated HBV RNA reduction. Overall, these results suggest that MCPIP1 may be involved in the antiviral effect downstream of IL-1β.

    DOI: 10.1038/s41598-020-77166-z

    PubMed

  4. FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms. Reviewed International journal

    Naoya Miyashita, Masafumi Horie, Hiroshi I Suzuki, Minako Saito, Yu Mikami, Kenichi Okuda, Richard C Boucher, Maho Suzukawa, Akira Hebisawa, Akira Saito, Takahide Nagase

    American journal of respiratory cell and molecular biology   Vol. 63 ( 6 ) page: 831 - 842   2020.9

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    Language:English   Publishing type:Research paper (scientific journal)  

    Fibroblasts provide a structural framework for multiple organs, and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of forkhead box L1 (FOXL1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high FOXL1 transcript levels associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, in contrast to fibroblasts derived from other organs. RNA in situ hybridization and immunohistochemistry in normal lung tissue indicated that FOXL1 mRNA and protein are expressed in submucosal interstitial cells together with airway epithelial cells. Transcriptome analysis revealed that FOXL1 could control a broad array of genes that potentiate fibroblast function, including TAZ/YAP signature genes and PDGF receptor-α. FOXL1 silencing in lung fibroblasts attenuated cell growth and collagen gel contraction capacity, underscoring the functional importance of FOXL1 in fibroproliferative reactions. Of clinical importance, increased FOXL1 mRNA expression was found in fibroblasts of idiopathic pulmonary fibrosis (IPF) lung tissue. Our observations suggest that FOXL1 regulates multiple functional aspects of lung fibroblasts as a key transcription factor, and is involved in IPF pathogenesis.

    DOI: 10.1165/rcmb.2019-0396OC

    PubMed

  5. Chd4 choreographs self-antigen expression for central immune tolerance. Reviewed International journal

    Yoshihiko Tomofuji, Hiroyuki Takaba, Hiroshi I Suzuki, Rayene Benlaribi, Cristian David Peña Martinez, Yoshihiro Abe, Yasuyuki Morishita, Tadashi Okamura, Akashi Taguchi, Tatsuhiko Kodama, Hiroshi Takayanagi

    Nature immunology   Vol. 21 ( 8 ) page: 892 - 901   2020.6

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    Language:English   Publishing type:Research paper (scientific journal)  

    Autoreactive T cells are eliminated in the thymus to prevent autoimmunity by promiscuous expression of tissue-restricted self-antigens in medullary thymic epithelial cells. This expression is dependent on the transcription factor Fezf2, as well as the transcriptional regulator Aire, but the entire picture of the transcriptional program has been obscure. Here, we found that the chromatin remodeler Chd4, also called Mi-2β, plays a key role in the self-antigen expression in medullary thymic epithelial cells. To maximize the diversity of self-antigen expression, Fezf2 and Aire utilized completely distinct transcriptional mechanisms, both of which were under the control of Chd4. Chd4 organized the promoter regions of Fezf2-dependent genes, while contributing to the Aire-mediated induction of self-antigens via super-enhancers. Mice deficient in Chd4 specifically in thymic epithelial cells exhibited autoimmune phenotypes, including T cell infiltration. Thus, Chd4 plays a critical role in integrating Fezf2- and Aire-mediated gene induction to establish central immune tolerance.

    DOI: 10.1038/s41590-020-0717-2

    PubMed

  6. Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes. Reviewed International journal

    Yotaro Ochi, Ayana Kon, Toyonori Sakata, Masahiro M Nakagawa, Naotaka Nakazawa, Masanori Kakuta, Keisuke Kataoka, Haruhiko Koseki, Manabu Nakayama, Daisuke Morishita, Tatsuaki Tsuruyama, Ryunosuke Saiki, Akinori Yoda, Rurika Okuda, Tetsuichi Yoshizato, Kenichi Yoshida, Yusuke Shiozawa, Yasuhito Nannya, Shinichi Kotani, Yasunori Kogure, Nobuyuki Kakiuchi, Tomomi Nishimura, Hideki Makishima, Luca Malcovati, Akihiko Yokoyama, Kengo Takeuchi, Eiji Sugihara, Taka-Aki Sato, Masashi Sanada, Akifumi Takaori-Kondo, Mario Cazzola, Mineko Kengaku, Satoru Miyano, Katsuhiko Shirahige, Hiroshi I Suzuki, Seishi Ogawa

    Cancer Discovery   Vol. 10 ( 6 ) page: 836 - 853   2020.6

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    STAG2 encodes a cohesin component and is frequently mutated in myeloid neoplasms, showing highly significant comutation patterns with other drivers, including RUNX1. However, the molecular basis of cohesin-mutated leukemogenesis remains poorly understood. Here we show a critical role of an interplay between STAG2 and RUNX1 in the regulation of enhancer-promoter looping and transcription in hematopoiesis. Combined loss of STAG2 and RUNX1, which colocalize at enhancer-rich, CTCF-deficient sites, synergistically attenuates enhancer-promoter loops, particularly at sites enriched for RNA polymerase II and Mediator, and deregulates gene expression, leading to myeloid-skewed expansion of hematopoietic stem/progenitor cells (HSPC) and myelodysplastic syndromes (MDS) in mice. Attenuated enhancer-promoter loops in STAG2/RUNX1-deficient cells are associated with downregulation of genes with high basal transcriptional pausing, which are important for regulation of HSPCs. Downregulation of high-pausing genes is also confirmed in STAG2-cohesin-mutated primary leukemia samples. Our results highlight a unique STAG2-RUNX1 interplay in gene regulation and provide insights into cohesin-mutated leukemogenesis. SIGNIFICANCE: We demonstrate a critical role of an interplay between STAG2 and a master transcription factor of hematopoiesis, RUNX1, in MDS development, and further reveal their contribution to regulation of high-order chromatin structures, particularly enhancer-promoter looping, and the link between transcriptional pausing and selective gene dysregulation caused by cohesin deficiency.This article is highlighted in the In This Issue feature, p. 747.

    DOI: 10.1158/2159-8290.CD-19-0982

    PubMed

  7. Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis. Reviewed International journal

    Matsuyama H, Suzuki HI

    International Journal of Molecular Sciences   Vol. 21 ( 1 )   2019.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3390/ijms21010132

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  8. TGF-β Signaling in Cellular Senescence and Aging-Related Pathology. Reviewed International journal

    Kana Tominaga, Hiroshi I Suzuki

    International Journal of Molecular Sciences   Vol. 20 ( 20 )   2019.10

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Aging is broadly defined as the functional decline that occurs in all body systems. The accumulation of senescent cells is considered a hallmark of aging and thought to contribute to the aging pathologies. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a myriad of cellular processes and has important roles in embryonic development, physiological tissue homeostasis, and various pathological conditions. TGF-β exerts potent growth inhibitory activities in various cell types, and multiple growth regulatory mechanisms have reportedly been linked to the phenotypes of cellular senescence and stem cell aging in previous studies. In addition, accumulated evidence has indicated a multifaceted association between TGF-β signaling and aging-associated disorders, including Alzheimer's disease, muscle atrophy, and obesity. The findings regarding these diseases suggest that the impairment of TGF-β signaling in certain cell types and the upregulation of TGF-β ligands contribute to cell degeneration, tissue fibrosis, inflammation, decreased regeneration capacity, and metabolic malfunction. While the biological roles of TGF-β depend highly on cell types and cellular contexts, aging-associated changes are an important additional context which warrants further investigation to better understand the involvement in various diseases and develop therapeutic options. The present review summarizes the relationships between TGF-β signaling and cellular senescence, stem cell aging, and aging-related diseases.

    DOI: 10.3390/ijms20205002

    PubMed

  9. Sequestration of microRNA-mediated target repression by the Ago2-associated RNA-binding protein FAM120A. Reviewed International journal

    Kelly TJ, Suzuki HI, Zamudio JR, Suzuki M, Sharp PA

    RNA (New York, N.Y.)   Vol. 25 ( 10 ) page: 1291 - 1297   2019.10

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1261/rna.071621.119

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  10. Fibroblast growth factor signals regulate transforming growth factor-β-induced endothelial-to-myofibroblast transition of tumor endothelial cells via Elk1. Reviewed International journal

    Akatsu Y, Takahashi N, Yoshimatsu Y, Kimuro S, Muramatsu T, Katsura A, Maishi N, Suzuki HI, Inazawa J, Hida K, Miyazono K, Watabe T

    Molecular Oncology   Vol. 13 ( 8 ) page: 1706 - 1724   2019.8

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/1878-0261.12504

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  11. Gain-of-function mutation of microRNA-140 in human skeletal dysplasia. Reviewed International journal

    Grigelioniene G, Suzuki HI, Taylan F, Mirzamohammadi F, Borochowitz ZU, Ayturk UM, Tzur S, Horemuzova E, Lindstrand A, Weis MA, Grigelionis G, Hammarsj? A, Marsk E, Nordgren A, Nordenskj?ld M, Eyre DR, Warman ML, Nishimura G, Sharp PA, Kobayashi T

    Nature Medicine   Vol. 25 ( 4 ) page: 583 - 590   2019.4

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41591-019-0353-2

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  12. Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-β-associated fibroblast activation in murine pulmonary fibrosis. Reviewed International journal

    Kunihiko Souma, Shigeyuki Shichino, Shinichi Hashimoto, Satoshi Ueha, Tatsuya Tsukui, Takuya Nakajima, Hiroshi I Suzuki, Francis H W Shand, Yutaka Inagaki, Takahide Nagase, Kouji Matsushima

    Scientific Reports   Vol. 8 ( 1 ) page: 16642 - 16642   2018.11

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    Lung fibroblasts play a pivotal role in pulmonary fibrosis, a devastating lung disease, by producing extracellular matrix. MicroRNAs (miRNAs) suppress numerous genes post-transcriptionally; however, the roles of miRNAs in activated fibroblasts in fibrotic lungs remain poorly understood. To elucidate these roles, we performed global miRNA-expression profiling of fibroblasts from bleomycin- and silica-induced fibrotic lungs and investigated the functions of miRNAs in activated lung fibroblasts. Clustering analysis of global miRNA-expression data identified miRNA signatures exhibiting increased expression during fibrosis progression. Among these signatures, we found that a miR-19a-19b-20a sub-cluster suppressed TGF-β-induced activation of fibroblasts in vitro. Moreover, to elucidate whether fibroblast-specific intervention against the sub-cluster modulates pathogenic activation of fibroblasts in fibrotic lungs, we intratracheally transferred the sub-cluster-overexpressing fibroblasts into bleomycin-treated lungs. Global transcriptome analysis of the intratracheally transferred fibroblasts revealed that the sub-cluster not only downregulated expression of TGF-β-associated pro-fibrotic genes, including Acta2, Col1a1, Ctgf, and Serpine1, but also upregulated expression of the anti-fibrotic genes Dcn, Igfbp5, and Mmp3 in activated lung fibroblasts. Collectively, these findings indicated that upregulation of the miR-19a-19b-20a sub-cluster expression in lung fibroblasts counteracted TGF-β-associated pathogenic activation of fibroblasts in murine pulmonary fibrosis.

    DOI: 10.1038/s41598-018-34839-0

    PubMed

  13. Evolution of weak cooperative interactions for biological specificity. Reviewed International journal

    Gao A, Shrinivas K, Lepeudry P, Suzuki HI, Sharp PA, Chakraborty AK

    Proc Natl Acad Sci U S A.   Vol. 115 ( 47 ) page: E11053 - E11060   2018.11

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    DOI: 10.1073/pnas.1815912115

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  14. An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas. Reviewed International journal

    Naoya Miyashita, Masafumi Horie, Hiroshi I Suzuki, Masahito Yoshihara, Dijana Djureinovic, Johan Persson, Hans Brunnström, Cecilia Lindskog, Hedvig Elfving, Patrick Micke, Akira Saito, Takahide Nagase

    Journal of Thoracic Oncology   Vol. 13 ( 11 ) page: 1676 - 1691   2018.11

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    INTRODUCTION: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. METHODS: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. RESULTS: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting that ASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. CONCLUSIONS: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

    DOI: 10.1016/j.jtho.2018.07.096

    PubMed

  15. Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling. Reviewed International journal

    Suzuki HI, Horie M, Mihira H, Saito A

    J Vis Exp.   ( 138 )   2018.8

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3791/57577

    PubMed

  16. MicroRNA Control of TGF-β Signaling. Reviewed International journal

    Suzuki HI

    International Journal of Molecular Sciences   Vol. 19 ( 7 )   2018.6

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    Authorship:Lead author, Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3390/ijms19071901

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  17. Deconvolution of seed and RNA-binding protein crosstalk in RNAi-based functional genomics. Reviewed International journal

    Suzuki HI, Spengler RM, Grigelioniene G, Kobayashi T, Sharp PA

    Nature Genetics   Vol. 50 ( 5 ) page: 657 - 661   2018.5

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41588-018-0104-1

    PubMed

  18. Transcriptional Pause Sites Delineate Stable Nucleosome-Associated Premature Polyadenylation Suppressed by U1 snRNP. Reviewed International journal

    Chiu AC, Suzuki HI, Wu X, Mahat DB, Kriz AJ, Sharp PA

    Molecular Cell   Vol. 69 ( 4 ) page: 648 - 663.e7   2018.2

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.molcel.2018.01.006

    PubMed

  19. HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis. Reviewed International journal

    Lai HH, Li JN, Wang MY, Huang HY, Croce CM, Sun HL, Lyu YJ, Kang JW, Chiu CF, Hung MC, Suzuki HI, Chen PS

    Journal of Clinical Investigation   Vol. 128 ( 2 ) page: 625 - 643   2018.2

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    DOI: 10.1172/JCI89212

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  20. TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts. Reviewed International journal

    Masafumi Horie, Naoya Miyashita, Yu Mikami, Satoshi Noguchi, Yasuhiro Yamauchi, Maho Suzukawa, Takeshi Fukami, Ken Ohta, Yoshihide Asano, Shinichi Sato, Yoko Yamaguchi, Mitsuhiro Ohshima, Hiroshi I Suzuki, Akira Saito, Takahide Nagase

    American journal of physiology. Lung cellular and molecular physiology   Vol. 314 ( 1 ) page: L177-L191 - L191   2018.1

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    Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts. Multiple key transcription factors important for lung mesenchyme development, including the T-box transcription factors TBX2, TBX4, and TBX5 were enriched in this lung-specific signature and were associated with super-enhancers. TBX4 showed highly specific expression in lung fibroblasts and was required for cell proliferation and collagen gel contraction capacity. Transcriptome analysis revealed that TBX4 could broadly regulate fibroblast-related pathways and partly contribute to super-enhancer-mediated transcriptional programs. Of pathological importance, lung fibroblast-specific genes were globally downregulated in lung cancer-associated fibroblasts (CAFs). Notably, TBX2, TBX4, and TBX5 were downregulated and hypermethylated in lung CAFs, suggesting an association between epigenetic silencing of these factors and phenotypic alteration of lung fibroblasts in cancer. Our study highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis.

    DOI: 10.1152/ajplung.00193.2017

    PubMed

  21. Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy Reviewed International journal

    Lior Nissim, Ming-Ru Wu, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, Timothy K. Lu

    Cell   Vol. 171 ( 5 ) page: 1138 - +   2017.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. These outputs included an immunogenic cell-surface protein, a cytokine, a chemokine, and a checkpoint inhibitor antibody. The circuits triggered selective T cell-mediated killing of cancer cells, but not of normal cells, in vitro. In in vivo efficacy assays, lentiviral circuit delivery mediated significant tumor reduction and prolonged mouse survival. Our design could be adapted to drive additional immunomodulators, sense other cancers, and potentially treat other diseases that require precise immunological programming.

    DOI: 10.1016/j.cell.2017.09.049

    Web of Science

    PubMed

  22. Regulation of TGF-beta-mediated endothelial-mesenchymal transition by microRNA-27 Reviewed International journal

    Hiroshi I. Suzuki, Akihiro Katsura, Hajime Mihira, Masafumi Horie, Akira Saito, Kohei Miyazono

    Journal of Biochemistry   Vol. 161 ( 5 ) page: 417 - 420   2017.5

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS  

    Multiple microRNAs (miRNAs) regulate epithelial-mesenchymal transition and endothelial-mesenchymal transition (EndMT). Here we report that microRNA-27b (miR-27b) positively regulates transforming growth factor-beta (TGF-beta)-induced EndMT of MS-1 mouse pancreatic microvascular endothelial cells. TGF-beta induced miR-23b/24-1/27b expression, and inhibition of miR-27 suppressed TGF-beta-mediated induction of mesenchymal genes. Genome-wide miRNA target analysis revealed that miR-27 targets Elk1, which acts as a competitive inhibitor of myocardin-related transcription factor-serum response factor signalling and as a myogenic repressor. miR-27b was also found to regulate several semaphorin receptors including Neuropilin 2, Plexin A2 and Plexin D1. These results suggest important roles of miR-27 in TGF-beta-driven EndMT.

    DOI: 10.1093/jb/mvx017

    Web of Science

    PubMed

  23. Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis Reviewed International journal

    Hiroshi I. Suzuki, Richard A. Young, Phillip A. Sharp

    Cell   Vol. 168 ( 6 ) page: 1000 - +   2017.3

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA ( pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNAexpression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancerdirected cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAsassociated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.

    DOI: 10.1016/j.cell.2017.02.015

    Web of Science

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  24. YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer Reviewed International journal

    Masafumi Horie, Akira Saito, Mitsuhiro Ohshima, Hiroshi I. Suzuki, Takahide Nagase

    Cancer Science   Vol. 107 ( 12 ) page: 1755 - 1766   2016.12

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    Small cell lung cancer (SCLC) is a highly aggressive and metastatic malignancy that shows rapid development of chemoresistance and a high rate of recurrence. Recent genome and transcriptome studies have provided the whole landscape of genomic alterations and gene expression changes in SCLC. In light of the inter-individual heterogeneity of SCLC, subtyping of SCLC might be helpful for prediction of therapeutic response and prognosis. Based on the transcriptome data of SCLC cell lines, we undertook transcriptional network-defined SCLC classification and identified a unique SCLC subgroup characterized by relatively high expression of Hippo pathway regulators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (YAP/TAZ subgroup). The YAP/TAZ subgroup displayed adherent cell morphology, lower expression of achaete-scute complex homolog 1 (ASCL1) and neuroendocrine markers, and higher expression of laminin and integrin. YAP knockdown caused cell morphological alteration reminiscent of floating growth pattern in many SCLC cell lines, and microarray analyses revealed a subset of genes regulated by YAP, including Ajuba LIM protein (AJUBA). AJUBA also contributed to cell morphology regulation. Of clinical importance, SCLC cell lines of the YAP/TAZ subgroup showed unique patterns of drug sensitivity. Our findings shed light on a subtype of SCLC with YAP and TAZ expression, and delineate molecular networks underlying the heterogeneity of SCLC.

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  25. MicroRNA-31 is a positive modulator of endothelial-mesenchymal transition and associated secretory phenotype induced by TGF-beta Reviewed International journal

    Akihiro Katsura, Hiroshi I. Suzuki, Toshihide Ueno, Hajime Mihira, Tomoko Yamazaki, Takahiko Yasuda, Tetsuro Watabe, Hiroyuki Mano, Yoshitsugu Yamada, Kohei Miyazono

    Genes to Cells   Vol. 21 ( 1 ) page: 99 - 116   2016.1

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    Transforming growth factor- (TGF-) plays central roles in endothelial-mesenchymal transition (EndMT) involved in development and pathogenesis. Although EndMT and epithelial-mesenchymal transition are similar processes, roles of microRNAs in EndMT are largely unknown. Here, we report that constitutively active microRNA-31 (miR-31) is a positive regulator of TGF--induced EndMT. Although the expression is not induced by TGF-, miR-31 is required for induction of mesenchymal genes including -SMA, actin reorganization and MRTF-A activation during EndMT. We identified VAV3, a regulator of actin remodeling and MRTF-A activity, as a miR-31 target. Global transcriptome analysis further showed that miR-31 positively regulates EndMT-associated unique secretory phenotype (EndMT-SP) characterized by induction of multiple inflammatory chemokines and cytokines including CCL17, CX3CL1, CXCL16, IL-6 and Angptl2. As a mechanism for this phenomenon, TGF- and miR-31 suppress Stk40, a negative regulator of NF-B pathway. Interestingly, TGF- induces alternative polyadenylation (APA)-coupled miR-31-dependent Stk40 suppression without concomitant miR-31 induction, and APA-mediated exclusion of internal poly(A) sequence in Stk40 3UTR enhances target efficiency of Stk40. Finally, miR-31 functions as a molecular hub to integrate TGF- and TNF- signaling to enhance EndMT. These data confirm that constitutively active microRNAs, as well as inducible microRNAs, serve as phenotypic modifiers interconnected with transcriptome dynamics during EndMT.

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  26. Reduced Supply of Monocyte-Derived Macrophages Leads to a Transition from Nodular to Diffuse Lesions and Tissue Cell Activation in Silica-Induced Pulmonary Fibrosis in Mice Reviewed International journal

    Shigeyuki Shichino, Jun Abe, Satoshi Ueha, Mikiya Otsuji, Tatsuya Tsukui, Mizuha Kosugi-Kanaya, Francis H. W. Shand, Shin-ichi Hashimoto, Hiroshi I. Suzuki, Teppei Morikawa, Yutaka Inagaki, Kouji Matsushima

    American Journal of Pathology   Vol. 185 ( 11 ) page: 2923 - 2938   2015.11

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    Pulmonary fibrosis (PF) is an intractable disorder with a poor prognosis. Lung macrophages have been reported to regulate both progression and remission of bleomycin-induced diffuse PP. However, it remains unclear how macrophages contribute to silica-induced progressive nodular PF and the associated tissue cell responses in vivo. We found that lack of monocyte-derived macrophages results in the formation of diffuse PP after silica instillation. We found that the proportion and the number of monocyte-derived macrophages were persistently higher in silica-induced progressive PF compared with bleomycin-induced PP. Surprisingly, in Ccr2(-/-) mice, in which monocyte-derived macrophage infiltration is impaired, silica administration induced diffuse PF with loose nodule formation and greater activation of tissue cells. In the diffuse lesions, the distribution of epithelial cells, distribution of myofibroblasts, and architecture of the basement membrane were disrupted. Consistent with the development of diffuse Lesions, genes that were differentially expressed in CD45(-) tissue cells from the lung of wild-type and Ccr2(-/-) mice were highly enriched in human diffuse, progressive PF. In gene ontology network analyses, many of these genes were associated with tissue remodeling and included genes not previously associated with PF, such as Mmp14, Thbs2, and Fgfr4. Overall, these results indicate that monocyte-derived macrophages prevent transition from nodular to diffuse silica-induced PF, potentially by regulating tissue cell responses.

    DOI: 10.1016/j.ajpath.2015.07.013

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  27. A clinically attainable dose of L-asparaginase targets glutamine addiction in lymphoid cell lines Reviewed International journal

    Koichi Sugimoto, Hiroshi I. Suzuki, Tsutomu Fujimura, Asami Ono, Naoko Kaga, Yasushi Isobe, Makoto Sasaki, Hikari Taka, Kohei Miyazono, Norio Komatsu

    Cancer Science   Vol. 106 ( 11 ) page: 1534 - 1543   2015.11

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    L-asparaginase (L-ASNase) is an important branch of chemotherapy for acute lymphoblastic leukemia (ALL) and some types of non-Hodgkin's lymphoma, including natural killer (NK)-cell lymphoma. Although it mediates hydrolysis of asparagine (Asn) and glutamine (Gln), which are variably required for cancer cell survival, the relative contribution of Asn and Gln depletion to the anti-tumor activity in therapeutic doses is unclear in ALL and malignant lymphoma. Here we demonstrate that L-ASNase exerts cytotoxicity through targeting the Gln addiction phenotype in lymphoid cell lines. A clinically attainable intermediate dose of L-ASNase induced massive apoptosis in ALL Jurkat and mantle cell lymphoma Jeko cell lines, while a low dose of L-ASNase effectively killed NK-cell lymphoma cells. In the lymphoid cell lines Jurkat and Jeco, deprivation of Gln but not Asn specifically suppressed cell growth and survival, and phenocopied the action of L-ASNase. L-ASNase treatment and Gln deprivation dramatically disrupted the refilling of the tricarboxylic acid (TCA) cycle by intracellular glutamate (Glu) and disturbed the mitochondrial integrity, which were alleviated by various anaplerotic TCA cycle intermediates, suggesting a direct contribution of glutaminase activity of L-ASNase. The action of L-ASNase differs between Jurkat cells and NK-cell lymphoma cells, according to their dependence on Gln and Asn. Furthermore, we observed that high expression of glutaminase GLS1 is associated with increased sensivity to L-ASNase in pediatric B lineage ALL. Our results redefine L-ASNase as a therapeutic agent targeting Gln addiction in certain lymphoid cells and offer an additional basis for predicting L-ASNase sensitivity and engineering selective L-ASNase derivatives for leukemia and lymphoma.

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  28. A role of uridylation pathway for blockade of let-7 microRNA biogenesis by Lin28B Reviewed International journal

    Hiroshi I. Suzuki, Akihiro Katsura, Kohei Miyazono

    Cancer Science   Vol. 106 ( 9 ) page: 1174 - 1181   2015.9

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    The precise control of microRNA (miRNA) biosynthesis is crucial for gene regulation. Lin28A and Lin28B are selective inhibitors of biogenesis of let-7 miRNAs involved in development and tumorigenesis. Lin28A selectively inhibits let-7 biogenesis through cytoplasmic uridylation of precursor let-7 by TUT4 terminal uridyl transferase and subsequent degradation by Dis3l2 exonuclease. However, a role of this uridylation pathway remains unclear in let-7 blockade by Lin28B, a paralog of Lin28A, while Lin28B is reported to engage a distinct mechanism in the nucleus to suppress let-7. Here we revisit a functional link between Lin28B and the uridylation pathway with a focus on let-7 metabolism in cancer cells. Both Lin28A and Lin28B interacted with Dis3l2 in the cytoplasm, and silencing of Dis3l2 upregulated uridylated pre-let-7 in both Lin28A- and Lin28B-expressing cancer cell lines. In addition, we found that amounts of let-7 precursors influenced intracellular localization of Lin28B. Furthermore, we found that MCPIP1 (Zc3h12a) ribonuclease was also involved in degradation of both non-uridylated and uridylated pre-let-7. Cancer transcriptome analysis showed association of expression levels of Lin28B and uridylation pathway components, TUT4 and Dis3l2, in various human cancer cells and hepatocellular carcinoma. Collectively, these results suggest that cytoplasmic uridylation pathway actively participates in blockade of let-7 biogenesis by Lin28B.

    DOI: 10.1111/cas.12721

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  29. Small-RNA asymmetry is directly driven by mammalian Argonautes Reviewed International journal

    Hiroshi I. Suzuki, Akihiro Katsura, Takahiko Yasuda, Toshihide Ueno, Hiroyuki Mano, Koichi Sugimoto, Kohei Miyazono

    Nature Structural & Molecular Biology   Vol. 22 ( 7 ) page: 512 - +   2015.7

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    Asymmetric selection of single-stranded guide RNAs from double-stranded RNA precursors is crucial in RNA silencing-mediated gene regulation. However, the precise mechanisms of small-RNA asymmetry are unclear, especially because asymmetric selection can still occur when the putative asymmetry sensors Drosophila R2D2 and mammalian Dicer are depleted. Here we report a direct contribution of mammalian Argonaute 2 (Ago2) to microRNA (miRNA) asymmetry. Ago2 selects strands with 5'-uridine or 5'-adenosine and thermodynamically unstable 5' ends in parallel through its two sensor regions, which contact the 5' nucleobases and 5'-phosphates of prospective guide strands. Hence, miRNA asymmetry shows superposed patterns reflecting 5'-end nucleotide identity ('digital' pattern) and thermodynamic stability ('analog' pattern). Furthermore, we demonstrate that cancer-associated miRNA variations reprogram asymmetric selection. Finally, our study presents a model of this universal principle, to aid in comprehensive understanding of miRNA function and development of new RNA-silencing therapies in precision medicine.

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  30. MicroRNA regulons in tumor microenvironment Reviewed International journal

    H. I. Suzuki, A. Katsura, H. Matsuyama, K. Miyazono

    Oncogene   Vol. 34 ( 24 ) page: 3085 - 3094   2015.6

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    Cancer initiation and progression are defined by the behavior of cancer cells per se and the development of tumor tissues, both of which are modulated by crosstalk between cancer cells and the surrounding microenvironment. Advances in cancer research have highlighted the significance of constant evolution of the tumor microenvironment, leading to tumor formation, metastasis and refractoriness to therapy. MicroRNAs (miRNAs) are small non-coding RNAs that function as major players of posttranscriptional gene regulation in diverse biological processes. They function as both tumor suppressors and promoters in many aspects of the autonomous behavior of cancer cells. Theoretically, dysfunction in the gene regulatory networks of cancer cells is one of the major driving forces for alterations of ostensibly normal surrounding cells. In this context, the core targets of miRNAs, termed miRNA regulons, are currently being expanded to include various modulators of the tumor microenvironment. Recent advances have highlighted two important roles played by miRNAs in the evolution of tumor microenvironments: miRNAs in tumor cells transform the microenvironment via non-cell-autonomous mechanisms, and miRNAs in neighboring cells stabilize cancer hallmark traits. These observations epitomize the distal and proximal functions of miRNAs in tumor microenvironments, respectively. Such regulation by miRNAs affects tumor angiogenesis, immune invasion and tumor-stromal interactions. This review summarizes recent findings on the mechanisms of miRNA-mediated regulation of tumor microenvironments, with a perspective on the design of therapeutic interventions.

    DOI: 10.1038/onc.2014.254

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  31. Control of HCV Replication With iMIRs, a Novel Anti-RNAi Agent Reviewed International journal

    Saori Itami, Yutaka Eguchi, Takayuki Mizutani, Eriko Aoki, Tadaaki Ohgi, Masahiko Kuroda, Takahiro Ochiya, Nobuyuki Kato, Hiroshi I. Suzuki, Norifumi Kawada, Yoshiki Murakami

    Molecular Therapy-Nucleic Acids   Vol. 4   page: e219   2015.1

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    MicroRNAs (miRNAs) serve important roles in regulating various physiological activities through RNA interference (RNAi). miR-122 is an important mediator of RNAi that is known to control hepatitis C virus (HCV) replication and is being investigated in clinical trials as a target for anti-HCV therapy. In this study, we developed novel oligonucleotides containing non-nucleotide residues, termed iMIRs, and tested their abilities to inhibit miR-122 function. We compared the inhibitory effects of iMIRs and locked nucleic acids (LNAs) on HCV replication in OR6 cells, which contained full-length HCV (genotype 1b) and a luciferase reporter gene. We found that RNA-type iMIRs with bulge-type, imperfect complementarity with respect to miR-122 were 10-fold more effective than LNAs in inhibiting HCV replication and functioned in a dose-dependent manner. Moreover, iMIR treatment of OR6 cells reduced HCV replication without inducing interferon responses or cellular toxicity. Based on these results, we suggest that iMIRs can inhibit HCV replication more effectively than LNAs and are therefore promising as novel antiviral agents.

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  32. An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non-Small Cell Lung Cancer Reviewed International journal

    Satoshi Noguchi, Akira Saito, Masafumi Horie, Yu Mikami, Hiroshi I. Suzuki, Yasuyuki Morishita, Mitsuhiro Ohshima, Yoshimitsu Abiko, Johanna Sofia Margareta Mattsson, Helena Koenig, Miriam Lohr, Karolina Edlund, Johan Botling, Patrick Micke, Takahide Nagase

    Clinical Cancer Research   Vol. 20 ( 17 ) page: 4660 - 4672   2014.9

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    Purpose: TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (n =SCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis.
    Experimental Design: We characterized TAZ at the DNA (n = 192), mRNA (n = 196), and protein levels (n = 345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta-analysis of public datasets (n = 1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ-dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis.
    Results: Higher TAZmRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway.
    Conclusion: TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies. (C) 2014 AACR.

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  33. Differential knockdown of TGF-beta ligands in a three-dimensional co-culture tumor- stromal interaction model of lung cancer Reviewed International journal

    Masafumi Horie, Akira Saito, Satoshi Noguchi, Yoko Yamaguchi, Mitsuhiro Ohshima, Yasuyuki Morishita, Hiroshi I. Suzuki, Tadashi Kohyama, Takahide Nagase

    BMC Cancer   Vol. 14   page: 580   2014.8

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    Background: Transforming growth factor (TGF)-beta plays a pivotal role in cancer progression through regulating cancer cell proliferation, invasion, and remodeling of the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are the predominant type of stromal cell, in which TGF-beta signaling is activated. Among the strategies for TGF-beta signaling inhibition, RNA interference (RNAi) targeting of TGF-beta ligands is emerging as a promising tool. Although preclinical studies support the efficacy of this therapeutic strategy, its effect on the tumor microenvironment in vivo remains unknown. In addition, differential effects due to knockdown of various TGF-beta ligand isoforms have not been examined. Therefore, an experimental model that recapitulates tumor-stromal interaction is required for validation of therapeutic agents.
    Methods: We have previously established a three-dimensional co-culture model of lung cancer, and demonstrated the functional role of co-cultured fibroblasts in enhancing cancer cell invasion and differentiation. Here, we employed this model to examine how knockdown of TGF-beta ligands affects the behavior of different cell types. We developed lentivirus vectors carrying artificial microRNAs against human TGF-beta 1 and TGF-beta 2, and tested their effects in lung cancer cells and fibroblasts.
    Results: Lentiviral vectors potently and selectively suppressed the expression of TGF-beta ligands, and showed anti-proliferative effects on these cells. Furthermore, knockdown of TGF-beta ligands attenuated fibroblast-mediated collagen gel contraction, and diminished lung cancer cell invasion in three-dimensional co-culture. We also observed differential effects by targeting different TGF-beta isoforms in lung cancer cells and fibroblasts.
    Conclusions: Our findings support the notion that RNAi-mediated targeting of TGF-beta ligands may be beneficial for lung cancer treatment via its action on both cancer and stromal cells. This study further demonstrates the usefulness of this three-dimensional co-culture model to examine the effect of therapeutic agents on tumor-stromal interaction.

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  34. EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis Reviewed International journal

    M. Tanaka, H. I. Suzuki, J. Shibahara, A. Kunita, T. Isagawa, A. Yoshimi, M. Kurokawa, K. Miyazono, H. Aburatani, S. Ishikawa, M. Fukayama

    Oncogne   Vol. 33 ( 19 ) page: 2454 - 2463   2014.5

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    Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease.

    DOI: 10.1038/onc.2013.204

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  35. Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression Reviewed International journal

    Yasuhiro Yoshimatsu, Yulia G. Lee, Yuichi Akatsu, Luna Taguchi, Hiroshi I. Suzuki, Sara I. Cunha, Kazuichi Maruyama, Yuka Suzuki, Tomoko Yamazaki, Akihiro Katsura, S. Paul Oh, Teresa A. Zimmers, Se-Jin Lee, Kristian Pietras, Gou Young Koh, Kohei Miyazono, Tetsuro Watabe

    Proc Natl Acad Sci U S A.   Vol. 110 ( 47 ) page: 18940 - 18945   2013.11

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    Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1(ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation.

    DOI: 10.1073/pnas.1310479110

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  36. Computational dissection of distinct microRNA activity signatures associated with peripheral T cell lymphoma subtypes Reviewed International journal

    H. I. Suzuki, H. Matsuyama, M. Noguchi, T. Yao, N. Komatsu, H. Mano, K. Sugimoto, K. Miyazono

    Leukemia   Vol. 27 ( 10 ) page: 2107 - 2111   2013.10

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    DOI: 10.1038/leu.2013.121

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  37. Widespread inference of weighted microRNA-mediated gene regulation in cancer transcriptome analysis Reviewed International journal

    Hiroshi I. Suzuki, Hajime Mihira, Tetsuro Watabe, Koichi Sugimoto, Kohei Miyazono

    Nucleic Acids Research   Vol. 41 ( 5 ) page: e62   2013.3

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS  

    MicroRNAs (miRNAs) comprise a gene-regulatory network through sequence complementarity with target mRNAs. Previous studies have shown that mammalian miRNAs decrease many target mRNA levels and reduce protein production predominantly by target mRNA destabilization. However, it has not yet been fully assessed whether this scheme is widely applicable to more realistic conditions with multiple miRNA fluctuations. By combining two analytical frameworks for detecting the enrichment of gene sets, Gene Set Enrichment Analysis (GSEA) and Functional Assignment of miRNAs via Enrichment (FAME), we developed GSEA-FAME analysis (GFA), which enables the prediction of miRNA activities from mRNA expression data using rank-based enrichment analysis and weighted evaluation of miRNA-mRNA interactions. This cooperative approach delineated a better widespread correlation between miRNA expression levels and predicted miRNA activities in cancer transcriptomes, thereby providing proof-of-concept of the mRNA-destabilization scenario. In an integrative analysis of The Cancer Genome Atlas (TCGA) multidimensional data including profiles of both mRNA and miRNA, we also showed that GFA-based inference of miRNA activity could be used for the selection of prognostic miRNAs in the development of cancer survival prediction models. This approach proposes a next-generation strategy for the interpretation of miRNA function and identification of target miRNAs as biomarkers and therapeutic targets.

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  38. An Integrated Expression Profiling Reveals Target Genes of TGF-beta and TNF-alpha Possibly Mediated by MicroRNAs in Lung Cancer Cells Reviewed International journal

    Akira Saito, Hiroshi I. Suzuki, Masafumi Horie, Mitsuhiro Ohshima, Yasuyuki Morishita, Yoshimitsu Abiko, Takahide Nagase

    PLoS One   Vol. 8 ( 2 ) page: e56587   2013.2

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    EMT (epithelial-mesenchymal transition) is crucial for cancer cells to acquire invasive phenotypes. In A549 lung adenocarcinoma cells, TGF-beta elicited EMT in Smad-dependent manner and TNF-alpha accelerated this process, as confirmed by cell morphology, expression of EMT markers, capacity of gelatin lysis and cell invasion. TNF-alpha stimulated the phosphorylation of Smad2 linker region, and this effect was attenuated by inhibiting MEK or JNK pathway. Comprehensive expression analysis unraveled genes differentially regulated by TGF-beta and TNF-alpha, such as cytokines, chemokines, growth factors and ECM (extracellular matrices), suggesting the drastic change in autocrine/paracrine signals as well as cell-to-ECM interactions. Integrated analysis of microRNA signature enabled us to identify a subset of genes, potentially regulated by microRNAs. Among them, we confirmed TGF-beta-mediated induction of miR-23a in lung epithelial cell lines, target genes of which were further identified by gene expression profiling. Combined with in silico approaches, we determined HMGN2 as a downstream target of miR-23a. These findings provide a line of evidence that the effects of TGF-beta and TNF-alpha were partially mediated by microRNAs, and shed light on the complexity of molecular events elicited by TGF-beta and TNF-alpha.

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  39. Sjogren Syndrome Antigen B (SSB)/La Promotes Global MicroRNA Expression by Binding MicroRNA Precursors through Stem-Loop Recognition Reviewed International journal

    Chunyang Liang, Ke Xiong, Keith E. Szulwach, Yi Zhang, Zhaohui Wang, Junmin Peng, Mingui Fu, Peng Jin, Hiroshi I. Suzuki, Qinghua Liu

    Journal of Biological Chemistry   Vol. 288 ( 1 ) page: 723 - 736   2013.1

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    MicroRNAs (miRNA) control numerous physiological and pathological processes. Typically, the primary miRNA (pri-miRNA) transcripts are processed by nuclear Drosha complex into similar to 70-nucleotide stem-loop precursor miRNAs (pre-miRNA), which are further cleaved by cytoplasmic Dicer complex into similar to 21-nucleotide mature miRNAs. However, it is unclear how nascent pre-miRNAs are protected from ribonucleases, such as MCPIP1, that degrade pre-miRNAs to abort miRNA production. Here, we identify Sjogren syndrome antigen B (SSB)/La as a pre-miRNA-binding protein that regulates miRNA processing in vitro. All three RNA-binding motifs (LAM, RRM1, and RRM2) of La/SSB are required for efficient pre-miRNA binding. Intriguingly, La/SSB recognizes the characteristic stem-loop structure of pre-miRNAs, of which the majority lack a 3' UUU terminus. Moreover, La/SSB associates with endogenous pri-/pre-miRNAs and promotes miRNA biogenesis by stabilizing pre-miRNAs from nuclease (e.g. MCPIP1)-mediated decay in mammalian cells. Accordingly, we observed positive correlations between the expression status of La/SSB and Dicer in human cancer transcriptome and prognosis. These studies identify an important function of La/SSB as a global regulator of miRNA expression, and implicate stem-loop recognition as a major mechanism that mediates association between La/SSB and diverse RNA molecules.

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  40. P53 actions on microRNA expression and maturation pathway Reviewed International journal

    Hiroshi I. Suzuki, Kohei Miyazono

    Methods in Molecular Biology   Vol. 962   page: 165 - 181   2013

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    The tumor suppressor p53 orchestrates multiple cellular pathways as a central node of anti-oncogenic programs in response to DNA damage, oncogene activation, and several stresses. In addition to the principal role as a transcription factor that transactivates many target genes involved in apoptosis and cell cycle control, p53 has been shown to exert various transactivation-independent effects both in the nucleus and in the cytoplasm. Diversity of p53 activities is further emphasized by the recent studies revealing the close interaction between the p53 and microRNA (miRNA) world. We recently demonstrated that p53 promotes the processing of several primary miRNA transcripts through association with Drosha, a central RNase III in miRNA biogenesis, under DNA damage-inducing conditions. In contrast to wild-type p53, cancer-derived p53 mutants attenuate miRNA maturation. These findings reveal a novel aspect of p53 activities and suggest complex crosstalks between miRNA biogenesis and intracellular signaling pathways. In this chapter, we describe the methods for evaluation of the effects of p53 on miRNA expression, an interaction between pri-miRNA and Drosha complex, and pri-miRNA processing activity of the Drosha complex. © 2013 Springer Science+Business Media New York.

    DOI: 10.1007/978-1-62703-236-0-14

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  41. Prostate Cancer Cells and Bone Stromal Cells Mutually Interact with Each Other through Bone Morphogenetic Protein-mediated Signals Reviewed International journal

    Hikaru Nishimori, Shogo Ehata, Hiroshi I. Suzuki, Yoko Katsuno, Kohei Miyazono

    Journal of Biological Chemistry   Vol. 287 ( 24 ) page: 20037 - 20046   2012.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Functional interactions between cancer cells and the bone microenvironment contribute to the development of bone metastasis. Although the bone metastasis of prostate cancer is characterized by increased ossification, the molecular mechanisms involved in this process are not fully understood. Here, the roles of bone morphogenetic proteins (BMPs) in the interactions between prostate cancer cells and bone stromal cells were investigated. In human prostate cancer LNCaP cells, BMP-4 induced the production of Sonic hedgehog (SHH) through a Smad-dependent pathway. In mouse stromal MC3T3-E1 cells, SHH up-regulated the expression of activin receptor IIB (ActR-IIB) and Smad1, which in turn enhanced BMP-responsive reporter activities in these cells. The combined stimulation with BMP-4 and SHH of MC3T3-E1 cells cooperatively induced the expression of osteoblastic markers, including alkaline phosphatase, bone sialoprotein, collagen type II alpha 1, and osteocalcin. When MC3T3-E1 cells and LNCaP cells were co-cultured, the osteoblastic differentiation of MC3T3-E1 cells, which was induced by BMP-4, was accelerated by SHH from LNCaP cells. Furthermore, LNCaP cells and BMP-4 cooperatively induced the production of growth factors, including fibroblast growth factor (FGF)-2 and epidermal growth factor (EGF) in MC3T3-E1 cells, and these may promote the proliferation of LNCaP cells. Taken together, our findings suggest that BMPs provide favorable circumstances for the survival of prostate cancer cells and the differentiation of bone stromal cells in the bone microenvironment, possibly leading to the osteoblastic metastasis of prostate cancer.

    DOI: 10.1074/jbc.M112.353094

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  42. TGF-beta-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A Reviewed International journal

    Hajime Mihira, Hiroshi I. Suzuki, Yuichi Akatsu, Yasuhiro Yoshimatsu, Takashi Igarashi, Kohei Miyazono, Tetsuro Watabe

    Journal of Biochemistry   Vol. 151 ( 2 ) page: 145 - 156   2012.2

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    Endothelial-mesenchymal transition (EndMT) plays important roles in various physiological and pathological processes. While signals mediated by transforming growth factor (TGF)-beta have been implicated in EndMT, the molecular mechanisms underlying it remain to be fully elucidated. Here, we examined the effects of TGF-beta signals on the EndMT of mouse pancreatic microvascular endothelial cells (MS-1). By addition of TGF-beta 2, MS-1 cells underwent mesenchymal transition characterized by re-organization of actin stress fibre and increased expression of various mesenchymal markers such as alpha-smooth muscle actin (alpha-SMA) through activation of Rho signals. Whereas activation of Rho signals via TGF-beta-induced non-Smad signals has been implicated in epithelial-mesenchymal transition (EMT), we found that Arhgef5, a guanine nucleotide exchange factor, is induced by Smad signals and contributes to the TGF-beta 2-induced alpha-SMA expression in MS-1 cells. We also found that TGF-beta 2 induces the expression of myocardin-related transcription factor-A (MRTF-A) in a Smad-dependent fashion and its nuclear accumulation in MS-1 cells and that MRTF-A is required and sufficient for TGF-beta 2-induced alpha-SMA expression. These results indicate that activation of Smad signals by TGF-beta 2 have dual effects on the activation of Rho signals and MRTF-A leading to the mesenchymal transition of MS-1 endothelial cells.

    DOI: 10.1093/jb/mvr121

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  43. Control of MicroRNA Maturation by p53 Tumor Suppressor and MCPIP1 Ribonuclease Reviewed International journal

    Hiroshi I. Suzuki, Kohei Miyazono

    Enzymes   Vol. 32   page: 163 - 183   2012

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    MicroRNAs (miRNAs) are small noncoding RNAs that function as major players of posttranscriptional gene regulation in diverse species. In mammals, the biogenesis of miRNAs is executed by cooperation of multiple biochemical reactions including processing of miRNA precursors by two central endoribonucleases, Drosha and Dicer. While the transcription of miRNA precursors is regulated by various transcription factors, it has been recently unlabeled that miRNA maturation is further subjected to a range of regulatory mechanisms in miRNA processome. We previously demonstrated that a key regulator of tumor suppression, p53, modulates Drosha-mediated processing of primary miRNA transcripts. The pathways for miRNA maturation also dynamically cross talk with other intracellular signaling pathways. Further, we recently revealed that MCPIP1, an immune regulator, antagonizes Dicer and suppresses miRNA processing as another important endoribonuclease. In addition, recent evidences highlighted alterations of miRNA biogenesis in cancer pathogenesis. These advances in miRNA metabolome would bring deep insights for understanding alterations of miRNAs in diverse disease pathogenesis and for development of miRNA-based therapeutic applications. In this chapter, we summarize our findings and advances in miRNA metabology. © 2012 Elsevier Inc.

    DOI: 10.1016/B978-0-12-404741-9.00008-8

    Scopus

  44. miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma Reviewed International journal

    Hironori Matsuyama, Hiroshi I. Suzuki, Hikaru Nishimori, Masaaki Noguchi, Takashi Yao, Norio Komatsu, Hiroyuki Mano, Koichi Sugimoto, Kohei Miyazono

    Blood   Vol. 118 ( 26 ) page: 6881 - 6892   2011.12

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    Many transformed lymphoma cells show immune-phenotypes resembling the corresponding normal lymphocytes; thus, they provide a guide for proper diagnosis and present promising routes to improve their pathophysiologic understanding and to identify novel therapeutic targets. However, the underlying molecular mechanism(s) of these aberrant immunephenotypes is largely unknown. Here, we report that microRNA-135b (miR-135b) mediates nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-driven oncogenicity and empowers IL-17-producing immunophenotype in anaplastic large cell lymphoma (ALCL). NPM-ALK oncogene strongly promoted the expression of miR-135b and its host gene LEMD1 through activation of signal transducer and activator of transcription (STAT) 3. In turn, elevated miR-135b targeted FOXO1 in ALCL cells. miR-135b introduction also decreased chemosensitivity in Jurkat cells, suggesting its contribution to oncogenic activities of NPM-ALK. Interestingly, miR-135b suppressed T-helper (Th) 2 master regulators STAT6 and GATA3, and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells, indicating that miR-135b-mediated Th2 suppression may lead to the skewing to ALCL immunophenotype overlapping with Th17 cells. Furthermore, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, demonstrating significance of this "Th17 mimic" pathway as a therapeutic target. These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment. (Blood.2011;118(26):6881-6892)

    DOI: 10.1182/blood-2011-05-354654

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  45. MCPIP1 Ribonuclease Antagonizes Dicer and Terminates MicroRNA Biogenesis through Precursor MicroRNA Degradation Reviewed International journal

    Hiroshi I. Suzuki, Mayu Arase, Hironori Matsuyama, Young Lim Choi, Toshihide Ueno, Hiroyuki Mano, Koichi Sugimoto, Kohei Miyazono

    Molecular Cell   Vol. 44 ( 3 ) page: 424 - 436   2011.11

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    MicroRNAs (miRNAs) are versatile regulators of gene expression and undergo complex maturation processes. However, the mechanism(s) stabilizing or reducing these small RNAs remains poorly understood. Here we identify mammalian immune regulator MCPIP1 (Zc3h12a) ribonuclease as a broad suppressor of miRNA activity and biogenesis, which counteracts Dicer, a central ribonuclease in miRNA processing. MCPIP1 suppresses miRNA biosynthesis via cleavage of the terminal loops of precursor miRNAs (pre-miRNAs). MCPIP1 also carries a vertebrate-specific oligomerization domain important for pre-miRNA recognition, indicating its recent evolution. Furthermore, we observed potential antagonism between MCPIP1 and Dicer function in human cancer and found a regulatory role of MCPIP1 in the signaling axis comprising miR-155 and its target c-Maf. These results collectively suggest that the balance between processing and destroying ribonucleases modulates miRNA biogenesis and potentially affects pathological miRNA dysregulation. The presence of this abortive processing machinery and diversity of MCPIP1-related genes may imply a dynamic evolutional transition of the RNA silencing system.

    DOI: 10.1016/j.molcel.2011.09.012

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  46. Cell Type-specific Target Selection by Combinatorial Binding of Smad2/3 Proteins and Hepatocyte Nuclear Factor 4 alpha in HepG2 Cells Reviewed International journal

    Anna Mizutani, Daizo Koinuma, Shuichi Tsutsumi, Naoko Kamimura, Masato Morikawa, Hiroshi I. Suzuki, Takeshi Imamura, Kohei Miyazono, Hiroyuki Aburatani

    Journal of Biological Chemistry   Vol. 286 ( 34 ) page: 29848 - 29860   2011.8

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    Specific regulation of target genes by transforming growth factor-beta (TGF-beta) in a given cellular context is determined in part by transcription factors and cofactors that interact with the Smad complex. In this study, we determined Smad2 and Smad3 (Smad2/3) binding regions in the promoters of known genes in HepG2 hepatoblastoma cells, and we compared them with those in HaCaT epidermal keratinocytes to elucidate the mechanisms of cell type- and context-dependent regulation of transcription induced by TGF-beta. Our results show that 81% of the Smad2/3 binding regions in HepG2 cells were not shared with those found in HaCaT cells. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is expressed in HepG2 cells but not in HaCaT cells, and the HNF4 alpha-binding motif was identified as an enriched motif in the HepG2-specific Smad2/3 binding regions. Chromatin immunoprecipitation sequencing analysis of HNF4 alpha binding regions under TGF-beta stimulation revealed that 32.5% of the Smad2/3 binding regions overlapped HNF4 alpha bindings. MIXL1 was identified as a new combinatorial target of HNF4 alpha and Smad2/3, and both the HNF4 alpha protein and its binding motif were required for the induction of MIXL1 by TGF-beta in HepG2 cells. These findings generalize the importance of binding of HNF4 alpha on Smad2/3 binding genomic regions for HepG2-specific regulation of transcription by TGF-beta and suggest that certain transcription factors expressed in a cell type-specific manner play important roles in the transcription regulated by the TGF-beta-Smad signaling pathway.

    DOI: 10.1074/jbc.M110.217745

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  47. Emerging complexity of microRNA generation cascades Reviewed International journal

    Hiroshi I. Suzuki, Kohei Miyazono

    Journal of Biochemistry   Vol. 149 ( 1 ) page: 15 - 25   2011.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS  

    MicroRNA (miRNA) modules are built in genetic networks as a complex regulatory layer directing post-transcriptional gene regulation. miRNAs coordinate a broad spectra of gene expression programs mainly through modulation of mRNA metabolism. Perturbations of miRNA networks are linked to a wide variety of pathological processes, including cardiovascular diseases and cancer. While the mechanisms regulating miRNA biogenesis were previously poorly understood, recent findings have shed light on the regulatory mechanisms of miRNAs themselves, especially their biogenesis. Multiple steps of miRNA maturation could potentially provide a variety of regulatory options to generate mature miRNAs differentially and produce gradation in miRNA processing efficiency. Several studies have demonstrated that miRNA maturation pathways crosstalk with intracellular signalling molecules, including p53, Smad proteins and estrogen receptor. Other lines of evidence have demonstrated the involvement of multiple RNA binding proteins in biased processing of different miRNA species. This review summarizes accumulating evidence for the emerging complexity and dynamics of regulated miRNA processing. These findings will lead to better understanding of miRNA dynamics in various pathogenetic pathways and provide the molecular basis for diagnostic and therapeutic strategies based on small RNA biology.

    DOI: 10.1093/jb/mvq113

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  48. Biliary cast syndrome and benign biliary stricture as complications of allogeneic hematopoietic stem cell transplantation Reviewed International journal

    Masataka Hosoi, Yasuhito Nannya, Takashi Sasaki, Hiroshi I. Suzuki, Koki Ueda, Takeshi Tsujino, Hiroyuki Isayama, Tsuyoshi Takahashi, Kazuhiko Koike, Mineo Kurokawa

    Annals Of Hematology   Vol. 89 ( 12 ) page: 1287 - 1289   2010.12

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    DOI: 10.1007/s00277-010-0942-0

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  49. Dynamics of microRNA biogenesis: crosstalk between p53 network and microRNA processing pathway Reviewed International journal

    Hiroshi I. Suzuki, Kohei Miyazono

    JOURNAL OF MOLECULAR MEDICINE-JMM   Vol. 88 ( 11 ) page: 1085 - 1094   2010.11

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    MicroRNAs (miRNAs) are pivotal regulators involved in various biological functions through the post-transcriptional regulation of gene expression. Alterations of miRNA expression and function contribute to both physiological and pathological processes such as development and cancer. While their roles have been attracting more attention in connection with tumor development, the mechanisms regulating miRNA biogenesis have not been well understood. Accumulating evidences have revealed the dynamic regulation of miRNA biosynthesis by several regulatory factors and demonstrated the complexity of miRNA-mediated gene regulation. In addition, several reports showed the interplay between the p53 tumor suppressor network and the miRNA-mediated gene regulatory system. We recently found that p53 modulates miRNA maturation at the processing step of primary miRNA transcripts, unraveling a novel function of p53. Here, we review the recent understanding of functional links between miRNA biogenesis and intracellular signaling pathways, with particular focus on the crosstalk between the p53 network and the miRNA biogenesis machinery. Further characterization of controlling elements for miRNA production and activity would provide important insights for a comprehensive understanding of the miRNA function in health and disease.

    DOI: 10.1007/s00109-010-0650-1

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  50. Regulation of autophagy by transforming growth factor-beta (TGF beta) signaling Reviewed International journal

    Hiroshi I. Suzuki, Kunihiko Kiyono, Kohei Miyazono

    Autophagy   Vol. 6 ( 5 ) page: 645 - 647   2010.7

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    Transforming growth factor-beta (TGF beta) has broad impacts on an array of diverse cellular functions including cell growth, differentiation, adhesion, migration and apoptosis. Perturbations of the TGF beta signaling pathways are involved in progression of various tumors. Autophagy is a pivotal response of normal and cancer cells to environmental stresses and is induced by various stimuli. Otherwise, autophagy has an intrinsic function in tumor suppression. Recently, we demonstrated that TGF beta induces autophagy in hepatocellular carcinoma cells and mammary carcinoma cells. Autophagy activation by TGF beta is mediated through the Smad and JNK pathways. We show that siRNA-mediated knockdown of autophagy genes suppresses the growth inhibitory function of TGF beta and that autophagy activation potentiates TGF beta-mediated induction of proapoptotic genes, Bim and Bmf, in hepatoma cells. In this context, the autophagy pathway might contribute to the growth inhibitory effect of TGF beta, in conjunction with other antiproliferative pathways downstream of TGF beta signaling. The context and manner by which the TGF beta signaling pathway regulates autophagy have implications for a better understanding of pathological and bidirectional roles of TGF beta signaling pathways in tumorigenesis.

    DOI: 10.4161/auto.6.5.12046

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  51. Erdheim-Chester disease: Multisystem involvement and management with interferon-alpha Reviewed International journal

    Hiroshi I. Suzuki, Noriko Hosoya, Kiyoshi Miyagawa, Satoshi Ota, Hiroko Nakashima, Noriko Makita, Mineo Kurokawa

    Leukemia Research   Vol. 34 ( 1 ) page: E21 - E24   2010.1

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    DOI: 10.1016/j.leukres.2009.07.026

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  52. Autophagy Is Activated by TGF-beta and Potentiates TGF-beta-Mediated Growth Inhibition in Human Hepatocellular Carcinoma Cells Reviewed International journal

    Kunihiko Kiyono, Hiroshi I. Suzuki, Hironori Matsuyama, Yasuyuki Morishita, Akiyoshi Komuro, Mitsunobu R. Kano, Koichi Sugimoto, Kohei Miyazono

    Cancer Research   Vol. 69 ( 23 ) page: 8844 - 8852   2009.12

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    Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell growth, differentiation, and apoptosis of various types of cells. Autophagy is emerging as a critical response of normal and cancer cells to environmental changes, but the relationship between TGF-beta signaling and autophagy has been poorly understood. Here, we showed that TGF-beta activates autophagy in human hepatocellular carcinoma cell tines. TGF-beta induced accumulation of autophagosomes and conversion of microtubule-associated protein I light chain 3 and enhanced the degradation rate of long-lived proteins. TGF-beta increased the mRNA expression levels of BECLIN1, ATG5, ATG7, and death-associated protein kinase (DAPK). Knockdown of Smad2/3, Smad4, or DAPK, or inhibition of c-Jun NH(2)-terminal kinase, attenuated TGF-beta-induced autophagy, indicating the involvement of both Smad and non-Smad pathway(s). TGF-beta activated autophagy earlier than execution of apoptosis (6-12 versus 48 h), and reduction of autophagy genes by small interfering RNA attenuated TGF-beta-mediated growth inhibition and induction of proapoptotic genes Bim and Bmf, suggesting the contribution of autophagy pathway to the growth-inhibitory effect of TGF-beta. Additionally, TGF-beta also induced autophagy in some mammary carcinoma cells, including MDA-MB-231 cells. These findings show that TGF-beta signaling pathway activates autophagy in certain human cancer cells and that induction of autophagy is a novel aspect of biological functions of TGF-beta. [Cancer Res 2009;69(23):8844-52]

    DOI: 10.1158/0008-5472.CAN-08-4401

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  53. c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma Reviewed International journal

    Kunihiko Kiyono, Hiroshi I. Suzuki, Yasuyuki Morishita, Akiyoshi Komuro, Caname Iwata, Masakazu Yashiro, Kosei Hirakawa, Mitsunobu R. Kano, Kohei Miyazono

    CANCER SCIENCE   Vol. 100 ( 10 ) page: 1809 - 1816   2009.10

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    c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-beta family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-beta signaling by dominant-negative TGF-beta type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-beta signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-beta type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-beta was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis. (Cancer Sci 2009; 100: 1809-1816).

    DOI: 10.1111/j.1349-7006.2009.01248.x

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  54. Modulation of microRNA processing by p53 Reviewed International journal

    Hiroshi I. Suzuki, Kaoru Yamagata, Koichi Sugimoto, Takashi Iwamoto, Shigeaki Kato, Kohei Miyazono

    Nature   Vol. 460 ( 7254 ) page: 529 - U111   2009.7

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour suppressors and oncogenes in tumour development(1), a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis(2-4). This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between Drosha complex and p68, leading to attenuation of miRNA processing activity. These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.

    DOI: 10.1038/nature08199

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  55. Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor beta Signaling Reviewed International journal

    Akiyoshi Komuro, Masakazu Yashiro, Caname Iwata, Yasuyuki Morishita, Erik Johansson, Yoshiko Matsumoto, Akira Watanabe, Hiroyuki Aburatani, Hiroyuki Miyoshi, Kunihiko Kiyono, Yo-taro Shirai, Hiroshi I. Suzuki, Kosei Hirakawa, Mitsunobu R. Kano, Kohei Miyazono

    JOURNAL OF THE NATIONAL CANCER INSTITUTE   Vol. 101 ( 8 ) page: 592 - 604   2009.4

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    Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor beta (TGF-beta) expression and thick stromal fibrosis. However, the association of TGF-beta signaling with diffuse-type gastric carcinoma has not been investigated in detail.
    We used a lentiviral infection system to express a dominant-negative TGF-beta type II receptor (dnT beta RII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided.
    Expression of dnT beta RII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnT beta RII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnT beta RII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnT beta RII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues.
    Disruption of TGF-beta signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.

    DOI: 10.1093/jnci/djp058

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  56. Resovist-enhanced MRI for preoperative assessment of colorectal hepatic metastases: a case of multiple bile duct hamartomas associated with colon cancer Reviewed

    Hiroshi Suzuki, Giichiro Tsurita, Soichiro Ishihara, Masaaki Akahane, Joji Kitayama, Hirokazu Nagawa

    Case Rep Gastroenterol   Vol. 2 ( 3 ) page: 509 - 516   2008.9

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  57. Late-onset pneumatosis cystoides intestinalis associated with non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation. Reviewed

    Hiroshi I Suzuki, Koji Izutsu, Takuro Watanabe, Kumi Oshima , Yoshinobu Kanda, Toru Motokura, Shigeru Chiba, Mineo Kurokawa

    International Journal of Hematology   Vol. 88 ( 1 ) page: 116 - 118   2008.7

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  58. Herpes simplex encephalitis and subsequent cytomegalovirus encephalitis after chemoradiotherapy for central nervous system lymphoma: a case report and literature review. Reviewed

    Hiroshi I Suzuk, Akira Hangaishi, Noriko Hosoya, Takuro Watanabe , Yoshinobu Kanda, Toru Motokura, Shigeru Chiba, Mineo Kurokawa

    International Journal of Hematology   Vol. 87 ( 5 ) page: 538 - 541   2008.6

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  59. Antileukemic immunity associated with antineutrophil antibody production after allogeneic hematopoietic SCT for myeloid/NK-cell precursor acute leukemia. Reviewed

    Hi Suzuki, T Suzuki, A Kamijo, S Oota, H Sato, A Hangaishi, T Takahashi, Y Kanda, T Motokura, S Chiba, M Kurokawa

    Bone Marrow Transplantation   Vol. 42 ( 4 ) page: 285 - 287   2008.5

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  60. Disseminated adenovirus disease by multiple adenovirus serotypes following allogeneic hematopoietic stem cell transplantation. Reviewed

    Hiroshi I Suzuki, Takashi Asai, Kiyomi Okada, Yukumasa Kazuyama, Tsuyoshi Takahashi, Yoshinobu Kanda, Shigeru Chiba, Mineo Kurokawa

    Biology of Blood and Marrow Transplantation   Vol. 14 ( 3 ) page: 353 - 355   2008.5

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    DOI: 10.1016/j.bbmt.2007.12.001

    DOI: 10.1016/j.bbmt.2007.12.001

  61. Drug-induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia. Reviewed

    Hiroshi I Suzuki, Takashi Asai, Zenshiro Tamaki, Akira Hangaishi, Shigeru Chiba, Mineo Kurokawa

    Haematologica   Vol. 93 ( 3 ) page: 469 - 470   2008.3

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  62. Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Reviewed

    Masako Oka, Caname Iwata, Hiroshi I Suzuki, Kunihiko Kiyono, Yasuyuki Morishita, Tetsuro Watabe, Akiyoshi Komuro, Mitsunobu R Kano, Kohei Miyazono

    Blood   Vol. 111 ( 9 ) page: 4571 - 4579   2008.2

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  63. Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells. Reviewed

    Kazuya Ogawa, Akira Saito, Hisanori Matsui, Hiroshi Suzuki, Satoshi Ohtsuka, Daisuke Shimosato, Yasuyuki Morishita, Tetsuro Watabe, Hitoshi Niwa, Kohei Miyazono

    Journal of Cell Science   Vol. 120   page: 55 - 65   2007.1

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  64. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Reviewed

    Hiroshi Takayanagi, Sunhwa Kim, Koichi Matsuo, Hiroshi Suzuki, Tomohiko Suzuki, Kojiro Sato, Taeko Yokochi, Hiromi Oda, Kozo Nakamura, Nobutaka Ida, Erwin F Wagner, Tadatsugu Taniguchi

    Nature   Vol. 416 ( 6882 ) page: 744 - 749   2002.4

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MISC 42

  1. Now and then 〜研究の日々〜

    鈴木洋

    実験医学   Vol. 40 ( 4 ) page: 580 - 582   2022.3

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  2. 第1部7章 miRNA生合成経路をみる(スーパーエンハンサーによるmiRNA生合成調節を例に)

    尾上耕一,鈴木洋

    実験医学部冊「リアルタイム・デジタルPCR実験スタンダード」     page: 131 - 140   2022.1

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  3. 第2部5章 デジタルPCRによるmiRNAの測定

    芳野聖子,小松真太郎,鈴木洋

    実験医学部冊「リアルタイム・デジタルPCR実験スタンダード」     page: 258 - 264   2022.1

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  4. スーパーエンハンサー制御ネットワークと造血器腫瘍

    鈴木 洋

    血液内科   Vol. 83 ( 1 ) page: 121 - 127   2021.7

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    Language:Japanese   Publisher:(有)科学評論社  

  5. 【相分離 メカニズムと疾患"膜のないオルガネラ"はいかに機能するか?神経変性疾患・ウイルス感染とどう関わるか?】(第2章)相分離と細胞内構造 染色体・転写制御と相分離 転写凝集体とゲノム高次構造

    鈴木 洋

    実験医学   Vol. 39 ( 10 ) page: 1586 - 1591   2021.6

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    Language:Japanese   Publisher:(株)羊土社  

    ゲノムは複雑な三次元構造をとり、その大部分を占める非コード領域のうち、マスター転写因子やメディエーターなどの転写調節因子が高密度で集積するスーパーエンハンサーは、細胞のアイデンティティーの決定や疾患の病態形成において重要な役割をもつ。DNA結合タンパク質とRNA結合タンパク質の多くは相分離の立役者であるLC(low-complexity)ドメインを有するが、スーパーエンハンサーに注目した解析を通じて、RNAポリメラーゼII、さまざまな転写因子、メディエーターなどの転写調節因子が相分離を引き起こす性質をもつことが明らかになってきた。本稿では、このような転写制御分子群が形成する相分離が関与した転写凝集体(transcription condensate)とゲノムの三次元構造という2つの構造情報がどのようにリンクして遺伝子制御を調節しているのか、最新の知見を踏まえて議論する。(著者抄録)

  6. 「柿の種」留学の意味: 早石修記念海外留学助成による留学体験記

    鈴木 洋

    生化学     2021.1

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  7. 北から南から:名古屋大学大学院医学系研究科附属神経疾患・腫瘍分子医学研究センター分子腫瘍学

    鈴木 洋

    生化学   Vol. 93 ( 4 ) page: 575   2021

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  8. 相分離とスーパーエンハンサーによる遺伝子制御

    鈴木 洋

    現代科学増刊46 相分離生物学の全貌     2020.11

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    Authorship:Lead author, Last author, Corresponding author   Language:Japanese  

  9. 相分離とスーパーエンハンサーによる遺伝子制御 (相分離生物学の全貌) -- (一対一から多対多へ)

    鈴木 洋

    現代化学 : 増刊   ( 46 ) page: 152 - 156   2020.11

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    Language:Japanese   Publisher:東京化学同人  

    CiNii Books

  10. Gain-of-function mutation of microRNA in human disease

    鈴木洋

    実験医学   Vol. 37 ( 14 ) page: 2322 - 2325   2020.9

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    Authorship:Lead author   Language:Japanese  

  11. 「柿の種」留学の意味: 早石修記念海外留学助成による留学体験記

    鈴木 洋

    生化学   Vol. 92 ( 6 ) page: 857   2020

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  12. Super-enhancers and Cancer

    鈴木洋

    Bio Clinica   Vol. 34 ( 9 ) page: 888 - 892   2019.8

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    Authorship:Lead author   Language:Japanese  

    J-GLOBAL

  13. Super-enhancer and phase separation-mediated transcription factory

    鈴木洋

    実験医学   Vol. 37 ( 9 ) page: 1411 - 1415   2019.6

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    J-GLOBAL

  14. Big data deconvolution of functional genomics and ceRBP concept

    鈴木洋

    月刊臨床免疫・アレルギー科   Vol. 71 ( 1 ) page: 92 - 96   2019.1

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    J-GLOBAL

  15. がん遺伝子の大規模なスクリーニングにおけるRNA結合タンパク質を介したオフターゲット効果

    鈴木洋, Phillip, A. Sharp

    ライフサイエンス新着論文レビュー     2018.4

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  16. 転写の一時停止を空間的に分離することによりスプライシングと転写伸長チェックポイントとの関係を理解する

    鈴木洋, Phillip, A. Sharp

    ライフサイエンス新着論文レビュー     2018.2

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    Authorship:Lead author   Language:Japanese  

  17. スーパーエンハンサーによるRNAプロセシングの制御

    鈴木洋, Phillip, A. Sharp

    ライフサイエンス新着論文レビュー     2017.3

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    Authorship:Lead author   Language:Japanese  

  18. 24章 リンパ腫の分子生物学(訳)

    鈴木洋

    デヴィータがんの分子生物学 第2版     page: 440 - 474   2017

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    Authorship:Lead author   Language:Japanese  

  19. MicroRNA networks in Cancer

    鈴木洋

    実験医学   Vol. 33 ( 20 ) page: 3312 - 3317   2015.12

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    Authorship:Lead author   Language:Japanese  

    J-GLOBAL

  20. Dissecting microRNA biogenesis and microRNA-mediated regulation of gene network

    鈴木洋, 鈴木洋

    生化学   Vol. 87 ( 4 ) page: 413 - 421   2015.8

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    J-GLOBAL

  21. マイクロRNAとは何か,古くて新しい非対称性の謎を解く

    鈴木洋, 宮園浩平

    ライフサイエンス新着論文レビュー     2015.7

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  22. Regulation of tumor and microenvironment crosstalk by microRNAs in T-cell lymphoma

    松山弘典, 鈴木洋, 宮園浩平

    月刊血液内科   Vol. 68 ( 6 ) page: 767 - 773   2014.6

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    Language:Japanese  

    J-GLOBAL

  23. microRNAs in hematological malignancies

    鈴木洋, 宮園浩平

    月刊血液内科   Vol. 68 ( 6 ) page: 719 - 724   2014.6

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    J-GLOBAL

  24. Classification of lymphoid malignancies by gene expression profiling

    鈴木洋, 宮園浩平

    月刊血液内科   Vol. 67 ( 6 ) page: 750 - 754   2013.12

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    J-GLOBAL

  25. Decoding RNA language: An approach for identification of miRNA-mRNA network

    鈴木洋, 宮園浩平

    細胞工学   Vol. 32 ( 8 ) page: 886 - 892   2013.7

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    Authorship:Lead author   Language:Japanese  

    J-GLOBAL

  26. 10 章 miRNA生合成経路をみる

    鈴木洋, 宮園浩平

    原理からよくわかるリアルタイムPCR完全実験ガイド     page: 137 - 146   2013

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    Authorship:Lead author   Language:Japanese  

  27. Circular RNA-RNA の新しい形とその機能

    鈴木洋

    実験医学   Vol. 31 ( 9 ) page: 1385 - 1386   2013

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    Authorship:Lead author   Language:Japanese  

  28. A novel regulatory mechanism of microRNA biogenesis and modulation of tumor microenvironment by microRNA

    鈴木洋

    細胞科学研究財団助成研究報告集     2013

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  29. Disease Modulation by small RNA biogenesis machinery

    鈴木洋, 宮園浩平

    月刊細胞   Vol. 44 ( 14 ) page: 589 - 592   2012.12

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    Authorship:Lead author   Language:Japanese  

    J-GLOBAL

  30. Dysregulation of microRNAs in chronic lymphocytic leukemia

    鈴木洋, 宮園浩平

    月刊血液内科   Vol. 65 ( 6 ) page: 846 - 852   2012.12

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    J-GLOBAL

  31. トップランナーに聞く : 最新医療に挑む若手研究者へのインタビュー(21)がん抑制遺伝子p53によるマイクロRNAプロセシング制御の解明

    鈴木 洋

    最新医学   Vol. 67 ( 9 ) page: 2050 - 2055   2012.9

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  32. Crosstalk between microRNA processing and signaling pathways in cancer

    鈴木洋, 宮園浩平

    月刊細胞   Vol. 44 ( 10 ) page: 448 - 451   2012.9

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    J-GLOBAL

  33. Alteration of miRNA biogenesis in cancer: implications for therapeutic targeting

    鈴木洋, 宮園浩平

    遺伝子医学MOOK   ( 23 ) page: 214 - 218   2012.9

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    J-GLOBAL

  34. 11章 がんとオートファジー

    鈴木洋

    がん増殖と悪性化の分子機構(宮澤恵二・伊藤進 編)     2012

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  35. 9章 がんとmicroRNA

    鈴木洋

    がん増殖と悪性化の分子機構(宮澤恵二・伊藤進 編)     2012

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  36. 30章 リンパ腫(訳)

    鈴木洋

    デヴィータがんの分子生物学     page: 448 - 468   2012

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  37. L‐アスパラギナーゼのリンパ系腫瘍への殺傷効果はglutaminolysisの抑制を介する

    杉本耕一, 鈴木洋, 藤村務, 大野麻美, 磯部泰司, 佐々木純, 森健, 宮園浩平, 小松則夫

    臨床血液   Vol. 52 ( 9 ) page: 1123 - 1123   2011.9

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    J-GLOBAL

  38. Regulation of microRNA processing by p53 –A novel face of p53-

    鈴木洋, 宮園浩平

    月刊血液・腫瘍科   Vol. 60 ( 6 ) page: 787 - 792   2010.6

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    J-GLOBAL

  39. 消化器疾患におけるRNA医学の進展を探る small RNAsはどのようにしてつくられ,どのようにして遺伝子発現を制御するのか

    鈴木洋, 宮園浩平

    分子消化器病   Vol. 7 ( 1 ) page: 7 - 14   2010.3

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    J-GLOBAL

  40. p53-microRNA interactive network

    鈴木洋, 宮園浩平

    細胞工学   Vol. 29 ( 4 ) page: 378 - 383   2010.3

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    J-GLOBAL

  41. Regulation of microRNA expression by p53: A novel tumor suppressor function of p53

    鈴木洋, 宮園浩平

    実験医学   Vol. 28 ( 3 ) page: 404 - 410   2010.2

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    J-GLOBAL

  42. p53によるマイクロRNAプロセッシングの制御

    鈴木洋, 宮園浩平

    分子消化器病   Vol. 6 ( 4 ) page: 79 - 82   2009

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KAKENHI (Grants-in-Aid for Scientific Research) 14

  1. Inhibition of microRNA functions by novel nucleic acids, iMIR

    Grant number:25640090  2013.4 - 2015.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    EGUCHI Yutaka, MURAKAMI Yoshiki, SUZUKI Hiroshi, OCHIYA Takahiro, KURODA Masahiko

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid) 

    We developed novel nucleic acid iMIR (Inhibitor of miRNA). We constructed various iMIRs targeting miR-16 and miR-21 by joining 3 miRNA-binding sequences (MBS) containing bulge-type imperfect complementarity with amino acid amidites, and found that Gly-Gly-type iMIR and TPA-type iMIR showed strong activity to inhibit miRNA functions, assessed by luciferase reporter assay. We also found that Gly-Gly-type RNA-iMIR and TPA-type RNA-iMIR targeting miR-122 strongly inhibited replication of hepatitis C virus (HCV), and 10-fold more effective than LNAs in inhibiting HCV replication. iMIR treatment of OR6 cells reduced HCV replication without inducing interferon responses or cellular toxicity, suggesting that iMIRs are promising as novel antiviral agents. These results were published in Molecular Therapy-Nucleic Acids (2015, 4, e219).

  2. 低分子RNAネットワークのシステム的理解と新たな癌制御アプローチへの応用

    Grant number:24689018  2012.4 - 2014.3

    科学研究費助成事業  若手研究(A)

    鈴木 洋

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    Authorship:Principal investigator 

    Grant amount:\26520000 ( Direct Cost: \20400000 、 Indirect Cost:\6120000 )

    本研究では、様々な病態における低分子RNAの発現異常の分子基盤となる低分子RNA生合成経路の新規調節機構、および悪性腫瘍との関係を明らかにすることを目的とする。また、低分子RNAの作動機構をネットワークレベルでシステム的に理解することを目的とする。平成24年度では、まず、miRNAによる標的mRNAの抑制効果を複数の内在性miRNAの発現量が変動する状況に外挿することが可能であるかを検討した。このために、GSEA-FAME analysis(GFA)という新規解析手法を開発し、癌のトランスクリプトームにおいてmiRNAがmRNA発現に与える負の影響が広範囲に観察されること、この原理を応用して、より頑健な新規バイオマーカーや新規治療標的をゲノムワイド発現解析から抽出できる可能性を明らかにした(Nucleic Acid Res, 41, e62)。また、これまでにMCPIP1と呼ばれるribonucleaseがmiRNAの生合成を抑制することを見出しているが、平成24年度では、MCPIP1によるmiRNA前駆体の分解を抑制するRNA結合タンパクLaとMCPIP1の関係について、乳癌の遺伝子発現データを解析し、DicerおよびLaとMCPIP1が拮抗関係にあることを見出した(J Biol Chem, 288, 723-736)。平成25年度では、GFA解析をT細胞リンパ腫の網羅的遺伝子発現解析データに拡張し、各リンパ腫サブタイプが特徴的なmiRNA活性パターンを示すことを明らかにするとともに、NPM-ALK陽性の悪性リンパ腫(未分化大細胞型リンパ腫)で発現異常が認められる複数のmiRNAの同定に成功し、mRNA発現データの解析からmiRNA―mRNAネットワークを類推できる可能性を新たに見出した(Leukemia, 27, 2107-2111)。
    25年度が最終年度であるため、記入しない。
    25年度が最終年度であるため、記入しない。
    25年度が最終年度であるため、記入しない。

  3. 低分子RNAの生合成機構の多様性と病態形成での役割に関する研究

    Grant number:23112702  2011.4 - 2013.3

    科学研究費助成事業  新学術領域研究(研究領域提案型)

    鈴木 洋

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    Authorship:Principal investigator 

    Grant amount:\9360000 ( Direct Cost: \7200000 、 Indirect Cost:\2160000 )

    本研究では、マイクロRNA(miRNA)などの低分子RNAプログラムの品質管理機構の分子基盤を明らかにし、その機構の悪性腫瘍およびウイルス感染における役割を解析し、病態把握への応用の可能性を検討することを目的とする。本研究にて、MCPIP1と呼ばれる遺伝子をmiRNAによるRNAサイレンシングの負の調節因子として同定し、MCPIP1が細胞質でribonucleaseとしてmiRNA前駆体のループ部分を切断しmiRNAの生合成を終息させること、MCPIP1がmiRNAの生合成における中心的なribonucleaseであるDicerと拮抗することなどを見出し、これまで未知であったmiRNA産生を負に調節する経路を新たに発見した(Molecular Cell, 44, 424-436)。平成24年度には、MCPIP1によるmiRNA前駆体の分解を抑制するRNA結合タンパクLaとMCPIP1の関係について、乳癌の遺伝子発現データを解析し、結果として、DicerおよびLaとMCPIP1の発現量が乳癌の予後に与える影響が拮抗関係にあることを見出した(J Biol Chem, 288, 723-736)。また、癌における遺伝子発現調節ネットワークにおいて、miRNAによるネットワーク制御の意義を解明し、新規バイオマーカーや新規治療標的を見出すことを目的とし、GSEA-FAME analysis(GFA)という新規解析手法を開発した(Nucleic Acid Res, 41, e62)。
    24年度が最終年度であるため、記入しない。
    24年度が最終年度であるため、記入しない。

  4. マイクロRNAによる癌微小環境の制御・維持機構の解明

    Grant number:22890038  2010 - 2011

    科学研究費助成事業  研究活動スタート支援

    鈴木 洋

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    Authorship:Principal investigator 

    Grant amount:\3146000 ( Direct Cost: \2420000 、 Indirect Cost:\726000 )

    本研究では、癌の進展を有利に導く癌微小環境の各側面(血管新生、免疫制御など)に関与するマイクロRNA(miRNA)の異常を同定し、それらのmiRNA群による癌微小環境の制御・維持機構を明らかとすることを目的とする。まず、造血器悪性腫瘍において、特徴的な染色体異常に起因する癌遺伝子の異常を伴う悪性リンパ腫に注目し、これらの腫瘍細胞で発現異常が認められるmiRNAの同定、および、その発現異常のメカニズム解析を行った。この結果、悪性リンパ腫において高発現を示すmiRNA-Xを同定し、miRNA-Xがこの癌遺伝子的異常、およびその下流の細胞内シグナル伝達経路の活性化に伴って誘導されることが明らかとなった。また、レンチウイルスを用いて特定のmiRNAの機能を阻害するシステムを樹立した。次に、このシステムとin silicoにおけるmiRNAの標的予測を組み合わせて詳細な検討を行った結果、miRNA-Xが様々な癌抑制因子を標的とすること、さらにリンパ腫細胞においてヘルハーT細胞サブセット特異的な転写因子を調節することで、リンパ腫細胞の免疫表現型を制御していることが明らかとなった。これらの結果は、悪性リンパ腫の臨床サンプルにおけるDNAマイクロアレイを用いたトランスクリプトーム解析の結果ともよく合致することをin silico解析により検討し確認した。現所沢、このmiRNA-Xが腫瘍細胞の免疫表現型に与える影響の、in vivoの腫瘍形成における意義(血管新生の促進など)、および、その修飾による治療応以下への可能性を検討している。

  5. Analysis of the mechanism of L-asparaginase to suppress the highly expressed eIF4E in NK-cell lymphoma

    Grant number:21591222  2009 - 2011

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    SUGIMOTO Koichi, SUZUKI Hiroshi, FUJIMURA Tsutomu, TAKAGI Masatoshi

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid) 

    We have shown two new mechanism of L-asparaginase(L-ASP), which is efficient even for chemotherapy-resistant NK-cell lymphoma. First, L-ASP decreased expression levels of various translation initiation factors including eIF4E, which in turn suppressed the translation of MYC, BCL-2 and eIF4E itself with tumor promoting and apoptosis inhibiting activities. Second, L-ASP depleted glutamine, induced TCA cycle depletion and insufficiency, and finally caused apoptosis. The result showed glutamine addiction of various lymphoid malignancies including acute lymphoblastic leukemia and the central role of TCA cycle in the suppression of apoptosis.

  6. ゲノム相分離生物学の創出とがん研究への応用

    Grant number:19K24694  2020 - 2022

    日本学術振興会  科学研究費助成事業 国際共同研究加速基金(帰国発展研究)  国際共同研究加速基金(帰国発展研究)

    鈴木 洋

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\56030000 ( Direct Cost: \43100000 、 Indirect Cost:\12930000 )

  7. Regulation of genome phase transition by RNA

    2017

    Osamu Hayaishi Memorial Scholarship for Study Abroad 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

  8. Super-enhancers in the RNA regulatory network

    2016

    Uehara Memorial Foundation Research Fellowship 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

  9. Decoding the RNA codons for future nucleic acid medicine

    2014 - 2015

    JSPS  Postdoctoral Fellowship for Research Abroad 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

  10. System biology for small RNA network and application to cancer therapeutics

    2012 - 2013

    MEXT  Grant-in-Aid for Young Scientists (A) 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

  11. Diversity in small RNA biogenesis and its role in pathogenesis

    2011 - 2012

    MEXT  Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area) 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

  12. Roles of miRNA in TGF-b signaling and its relationship with pathogenesis

    2011

    Cell Science Research Foundation 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

  13. Regulation of tumor microenvironment by microRNA

    2010 - 2011

    JSPS  Grant-in-Aid for Research Activity start-up 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

  14. Roles of miRNAs and autophagy in tumor progression

    2008 - 2010

    JSPS  Grant-in-Aid for JSPS Fellows 

    Hiroshi SUZUKI

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    Authorship:Principal investigator  Grant type:Competitive

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