Faculty Profiles - SUZUKI Hiroshi

Papers - SUZUKI Hiroshi

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Phase-separated super-enhancers confer an innate radioresistance on genomic DNA. Reviewed

Matsumoto K, Ikliptikawati DK, Makiyama K, Mochizuki K, Tobita M, Kobayashi I, Voon DC, Lim K, Ogawa K, Kashiwakura I, Suzuki HI, Yoshino H, Wong RW, Hazawa M

Journal of radiation research Vol. 65 ( 4 ) page： 482 - 490 2024.7

Distinct microRNA signature and suppression of ZFP36L1 define ASCL1-positive lung adenocarcinoma. Reviewed

Enokido T, Horie M, Yoshino S, Suzuki HI, Matsuki R, Brunnström H, Micke P, Nagase T, Saito A, Miyashita N

Molecular cancer research : MCR 2023.10

TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation. Reviewed International journal

Miho M Suzuki, Kenta Iijima, Koichi Ogami, Keiko Shinjo, Yoshiteru Murofushi, Jingqi Xie, Xuebing Wang, Yotaro Kitano, Akira Mamiya, Yuji Kibe, Tatsunori Nishimura, Fumiharu Ohka, Ryuta Saito, Shinya Sato, Junya Kobayashi, Ryoji Yao, Kanjiro Miyata, Kazunori Kataoka, Hiroshi I Suzuki, Yutaka Kondo

Nature communications Vol. 14 ( 1 ) page： 4521 - 4521 2023.8

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

Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.

DOI： 10.1038/s41467-023-40243-8

Roles of MicroRNAs in Disease Biology. Reviewed

Hiroshi I Suzuki

JMA journal Vol. 6 ( 2 ) page： 104 - 113 2023.4

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

Gene regulation by microRNAs (miRNAs) plays important roles in development, physiology, and disease. miRNAs are an abundant class of noncoding RNAs that are generated through multistep biosynthetic pathways and typically repress gene expression through target destabilization and translational inhibition. Complex interactions between miRNAs and target mRNAs are associated with characteristic molecular mechanisms, including miRNA cotargeting, target-directed miRNA degradation, and crosstalk with various RNA-binding proteins. Consistent with the broad influence on cellular function, miRNA deregulation is commonly observed in various diseases, particularly cancer, with both tumor-suppressive and oncogenic roles. Mutations in the miRNA biosynthetic pathway and several miRNA genes have been linked to diverse types of cancer and a subset of genetic diseases, respectively. Additionally, super-enhancers play important roles in the regulation of cell type-specific and disease-associated miRNAs. This review summarizes the molecular features of miRNA biogenesis and target regulation along with the roles of miRNAs in disease biology, with recent examples expanding the pathophysiological roles of miRNAs.

DOI： 10.31662/jmaj.2023-0009

Optimization of Cas9 activity through the addition of cytosine extensions to single-guide RNAs. Reviewed International journal

Masaki Kawamata, Hiroshi I Suzuki, Ryota Kimura, Atsushi Suzuki

Nature biomedical engineering Vol. 7 ( 5 ) page： 672 - + 2023.4

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

The precise regulation of the activity of Cas9 is crucial for safe and efficient editing. Here we show that the genome-editing activity of Cas9 can be constrained by the addition of cytosine stretches to the 5'-end of conventional single-guide RNAs (sgRNAs). Such a 'safeguard sgRNA' strategy, which is compatible with Cas12a and with systems for gene activation and interference via CRISPR (clustered regularly interspaced short palindromic repeats), leads to the length-dependent inhibition of the formation of functional Cas9 complexes. Short cytosine extensions reduced p53 activation and cytotoxicity in human pluripotent stem cells, and enhanced homology-directed repair while maintaining bi-allelic editing. Longer extensions further decreased on-target activity yet improved the specificity and precision of mono-allelic editing. By monitoring indels through a fluorescence-based allele-specific system and computational simulations, we identified optimal windows of Cas9 activity for a number of genome-editing applications, including bi-allelic and mono-allelic editing, and the generation and correction of disease-associated single-nucleotide substitutions via homology-directed repair. The safeguard-sgRNA strategy may improve the safety and applicability of genome editing.

DOI： 10.1038/s41551-023-01011-7

Network Regulation of microRNA Biogenesis and Target Interaction Reviewed

Komatsu Shintaro, Kitai Hiroki, Suzuki Hiroshi I.

CELLS Vol. 12 ( 2 ) 2023.1

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis. Reviewed International journal

Hiroki Kitai, Noritoshi Kato, Koichi Ogami, Shintaro Komatsu, Yu Watanabe, Seiko Yoshino, Eri Koshi, Shoma Tsubota, Yoshio Funahashi, Takahiro Maeda, Kazuhiro Furuhashi, Takuji Ishimoto, Tomoki Kosugi, Shoichi Maruyama, Kenji Kadomatsu, Hiroshi I Suzuki

BMC biology Vol. 20 ( 1 ) page： 248 - 248 2022.11

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

BACKGROUND: Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression ("neighborhood" miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. RESULTS: Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites ("seed overlap" miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, "seed overlap" miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive "seed overlap" is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes-those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both "seed overlap" and "neighborhood" miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. CONCLUSIONS: Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

DOI： 10.1186/s12915-022-01447-4

ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Reviewed International journal

Minglu Yan, Noriko Komatsu, Ryunosuke Muro, Nam Cong-Nhat Huynh, Yoshihiko Tomofuji, Yukinori Okada, Hiroshi I Suzuki, Hiroyuki Takaba, Riko Kitazawa, Sohei Kitazawa, Warunee Pluemsakunthai, Yuichi Mitsui, Takashi Satoh, Tadashi Okamura, Takeshi Nitta, Sin-Hyeog Im, Chan Johng Kim, George Kollias, Sakae Tanaka, Kazuo Okamoto, Masayuki Tsukasaki, Hiroshi Takayanagi

Nature immunology Vol. 23 ( 9 ) page： 1330 - 1341 2022.9

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

Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications.

DOI： 10.1038/s41590-022-01285-0

Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network. Reviewed International journal

Yuko Shimamura, Kazuhiro Furuhashi, Akihito Tanaka, Munetoshi Karasawa, Tomoya Nozaki, Shintaro Komatsu, Kenshi Watanabe, Asuka Shimizu, Shun Minatoguchi, Makoto Matsuyama, Yuriko Sawa, Naotake Tsuboi, Takuji Ishimoto, Hiroshi I Suzuki, Shoichi Maruyama

Communications biology Vol. 5 ( 1 ) page： 753 - 753 2022.7

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

Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

DOI： 10.1038/s42003-022-03712-2

ASCL1 regulates super-enhancer-associated miRNAs to define molecular subtypes of small cell lung cancer. Reviewed International journal

Kazuko Miyakawa, Naoya Miyashita, Masafumi Horie, Yasuhiro Terasaki, Hidenori Tanaka, Hirokazu Urushiyama, Kensuke Fukuda, Yugo Okabe, Takashi Ishii, Naomi Kuwahara, Hiroshi I Suzuki, Takahide Nagase, Akira Saito

Cancer science 2022.7

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

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with dismal prognosis. Recently, molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1 and POU2F3 transcription regulators. ASCL1 is essential for neuroendocrine differentiation and is expressed in the majority of SCLC. Although previous studies investigated ASCL1 target genes in SCLC cells, ASCL1-mediated regulation of miRNAs and its relationship to molecular subtypes remain poorly explored. Here, we performed genome-wide profiling of chromatin modifications (H3K27me3, H3K4me3 and H3K27ac) by CUT&Tag assay and ASCL1 knockdown followed by RNA-sequencing and miRNA array analyses in SCLC cells. ASCL1 could preferentially regulate genes associated with super-enhancers (SEs) defined by enrichment of H3K27ac marking. Moreover, ASCL1 positively regulated several SE-associated miRNAs such as miR-7, miR-375, miR-200b-3p and miR-429, leading to repression of their targets whereas ASCL1 suppressed miR-455-3p, an abundant miRNA in other molecular subtypes. We further elucidated unique patterns of SE-associated miRNAs in different SCLC molecular subtypes, highlighting subtype-specific miRNA networks with functional relevance. Notably, we found apparent de-repression of common target genes of different miRNAs following ASCL1 knockdown, suggesting combinatorial action of multiple miRNAs underlying molecular heterogeneity of SCLC; for example, co-targeting of YAP1 by miR-9 and miR-375. Our comprehensive analyses provide novel insights into SCLC pathogenesis and a clue to understanding subtype-dependent phenotypic differences.

DOI： 10.1111/cas.15481

The molecular understanding of super-enhancer dysregulation in cancer. Reviewed

Seiko Yoshino, Hiroshi I Suzuki

Nagoya journal of medical science Vol. 84 ( 2 ) page： 216 - 229 2022.5

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

Abnormalities in the regulation of gene expression are associated with various pathological conditions. Among the distal regulatory elements in the genome, the activation of target genes by enhancers plays a central role in the formation of cell type-specific gene expression patterns. Super-enhancers are a subclass of enhancers that frequently contain multiple enhancer-like elements and are characterized by dense binding of master transcription factors and Mediator complexes and high signals of active histone marks. Super-enhancers have been studied in detail as important regulatory regions that control cell identity and contribute to the pathogenesis of diverse diseases. In cancer, super-enhancers have multifaceted roles by activating various oncogenes and other cancer-related genes and shaping characteristic gene expression patterns in cancer cells. Alterations in super-enhancer activities in cancer involve multiple mechanisms, including the dysregulation of transcription factors and the super-enhancer-associated genomic abnormalities. The study of super-enhancers could contribute to the identification of effective biomarkers and the development of cancer therapeutics targeting transcriptional addiction. In this review, we summarize the roles of super-enhancers in cancer biology, with a particular focus on hematopoietic malignancies, in which multiple super-enhancer alteration mechanisms have been reported.

DOI： 10.18999/nagjms.84.2.216

Biomolecular condensates in cancer biology. Reviewed International journal

Hiroshi I Suzuki, Koh Onimaru

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

Authorship：Lead author,　Corresponding author 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

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

Koichi Ogami, Hiroshi I Suzuki

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

Authorship：Last author,　Corresponding author 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

MCPIP1 reduces HBV-RNA by targeting its epsilon structure. Reviewed 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Phenotypic plasticity of endothelial cells underlies cardiovascular system development, cardiovascular diseases, and various conditions associated with organ fibrosis. In these conditions, differentiated endothelial cells acquire mesenchymal-like phenotypes. This process is called endothelial-mesenchymal transition (EndMT) and is characterized by downregulation of endothelial markers, upregulation of mesenchymal markers, and morphological changes. EndMT is induced by several signaling pathways, including transforming growth factor (TGF)-β, Wnt, and Notch, and regulated by molecular mechanisms similar to those of epithelial-mesenchymal transition (EMT) important for gastrulation, tissue fibrosis, and cancer metastasis. Understanding the mechanisms of EndMT is important to develop diagnostic and therapeutic approaches targeting EndMT. Robust induction of EndMT in vitro is useful to characterize common gene expression signatures, identify druggable molecular mechanisms, and screen for modulators of EndMT. Here, we describe an in vitro method for induction of EndMT. MS-1 mouse pancreatic microvascular endothelial cells undergo EndMT after prolonged exposure to TGF-β and show upregulation of mesenchymal markers and morphological changes as well as induction of multiple inflammatory chemokines and cytokines. Methods for the analysis of microRNA (miRNA) modulation are also included. These methods provide a platform to investigate mechanisms underlying EndMT and the contribution of miRNAs to EndMT.

DOI： 10.3791/57577

MicroRNA Control of TGF-β Signaling. Reviewed International journal

Suzuki HI

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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.

DOI： 10.1111/cas.13078

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

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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.

DOI： 10.1111/gtc.12323

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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

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

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

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.

DOI： 10.1111/cas.12807

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

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

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

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

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

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.

DOI： 10.1038/nsmb.3050

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

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

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

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

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

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.

DOI： 10.1038/mtna.2014.71

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

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

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.

DOI： 10.1158/1078-0432.CCR-13-3328

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

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

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.

DOI： 10.1186/1471-2407-14-580

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

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

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

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

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.

DOI： 10.1093/nar/gks1439

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

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.

DOI： 10.1371/journal.pone.0056587

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

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

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.

DOI： 10.1074/jbc.M112.401323

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

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

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

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

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

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

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

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

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

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

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

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC HEMATOLOGY

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：LANDES BIOSCIENCE

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

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

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

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

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

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

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

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

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

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

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

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

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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