Faculty Profiles - SUZUKI Hiroshi

Papers - SUZUKI Hiroshi

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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

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