Faculty Profiles - Otsuka Motoyuki

Papers - Otsuka Motoyuki

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Impact of PNPLA3 polymorphisms on the development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection Reviewed

Masaya Sato, Naoya Kato, Ryosuke Tateishi, Ryosuke Muroyama, Norie Kowatari, Wenwen Li, Kaku Goto, Motoyuki Otsuka, Shuichiro Shiina, Haruhiko Yoshida, Masao Omata, Kazuhiko Koike

HEPATOLOGY RESEARCH 44 ( 10 ) E137 - E144 2014.10

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

Aim: The PNPLA3 rs738409 C>G polymorphism (encoding for I148M) has recently been identified as a susceptibility factor for steatosis-mediated liver damage. We evaluated the influence of this polymorphism on hepatocarcinogenesis in patients with chronic hepatitis C (CHC) virus infection.
Methods: We genotyped the rs738409 single nucleotide polymorphism in 358 hepatitis C-associated hepatocellular carcinoma (HCC) patients and correlated the age at onset of HCC and the interval between hepatitis C virus (HCV) infection and the development of HCC in patients with each genotype.
Results: The frequencies of CC, CG and GG genotypes were 27.9% (100/358), 49.2% (176/358) and 22.9% (82/358), respectively, and were in Hardy-Weinberg equilibrium. The median age at onset of HCC for the GG genotype was significantly younger compared to for non-GG genotypes (67.81 vs 69.87 years, P < 0.001), and the median interval between HCV infection and the development of HCC was significantly shorter in patients with the GG genotype (39.96 vs 40.85 years, P = 0.008). PNPLA3 GG genotype was also associated with a higher aspartate aminotransferase level (69.5 vs 59.0 IU/L, P = 0.02), lower prothrombin time (73.0% vs 78.0%, P = 0.008) and a higher prevalence of histological steatosis (40.0% vs. 22.2%, P = 0.01) at the time of HCC onset.
Conclusion: The PNPLA3 genotype GG may be associated with accelerated hepatocarcinogenesis in CHC patients through increased steatosis in the liver.

DOI： 10.1111/hepr.12258

The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels Reviewed

Chikako Shibata, Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Kaku Goto, Ryosuke Muroyama, Naoya Kato, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike

VIROLOGY 462 42 - 48 2014.8

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

Despite recent progress in the development of direct-acting antivirals against hepatitis C virus (HCV), chronic HCV infection remains an important health burden worldwide. MicroRNA122 (miR122), a liver-specific microRNA (miRNA), positively regulates HCV replication, and systemic application of antisense oligonucleotides against miR122 led to the long-lasting suppression of HCV viremia in human clinical trials. Here, we report that apigenin, a flavonoid and an inhibitor of maturation of a subset of miRNAs, inhibits HCV replication in vitro. Apigenin decreased the expression levels of mature miR122 without significantly affecting cell growth. Because supplementation of synthesized miR122 oligonucleotides or overexpression of constitutively active TRBP blocked these effects, the inhibitory effects of apigenin on HCV replication seemed to be dependent on the reduction of mature miR122 expression levels through inhibition of TRBP phosphorylation. Thus, apigenin intake, either through regular diet or supplements, may decrease HCV replication in chronically infected patients. (C) 2014 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.virol.2014.05.024

Specific delivery of microRNA93 into HBV-replicating hepatocytes downregulates protein expression of liver cancer susceptible gene MICA Reviewed

Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Chikako Shibata, Takeshi Yoshikawa, Akemi Takata, Ryosuke Muroyama, Norie Kowatari, Masaya Sato, Naoya Kato, Shun'ichi Kuroda, Kazuhiko Koike

ONCOTARGET 5 ( 14 ) 5581 - 5590 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：IMPACT JOURNALS LLC

Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). To date, the lack of efficient in vitro systems supporting HBV infection and replication has been a major limitation of HBV research. Although primary human hepatocytes support the complete HBV life cycle, their limited availability and difficulties with gene transduction remain problematic. Here, we used human primary hepatocytes isolated from humanized chimeric uPA/SCID mice as efficient sources. These hepatocytes supported HBV replication in vitro. Based on analyses of mRNA and microRNA (miRNA) expression levels in HBV-infected hepatocytes, miRNA93 was significantly downregulated during HBV infection. MiRNA93 is critical for regulating the expression levels of MICA protein, which is a determinant for HBV-induced HCC susceptibility. Exogenous addition of miRNA93 in HBV-infected hepatocytes using bionanocapsules consisted of HBV envelope L proteins restored MICA protein expression levels in the supernatant. These results suggest that the rescued suppression of soluble MICA protein levels by miRNA93 targeted to HBV-infected hepatocytes using bionanocapsules may be useful for the prevention of HBV-induced HCC by altering deregulated miRNA93 expression.

IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection Reviewed

Masaya Sato, Naoya Kato, Ryosuke Tateishi, Ryosuke Muroyama, Norie Kowatari, Wenwen Li, Kaku Goto, Motoyuki Otsuka, Shuichiro Shiina, Haruhiko Yoshida, Masao Omata, Kazuhiko Koike

JOURNAL OF GASTROENTEROLOGY 49 ( 4 ) 748 - 754 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

IL28B polymorphisms were shown to be associated with a response to peg-interferon-based treatment in chronic hepatitis C (CHC) and spontaneous clearance. However, little is known about how this polymorphism affects the course of CHC, including the development of hepatocellular carcinoma (HCC). We evaluated the influence of IL28B polymorphisms on hepatocarcinogenesis in CHC patients.
We genotyped the rs8099917 single-nucleotide polymorphism in 351 hepatitis C-associated HCC patients without history of IFN-based treatment, and correlated the age at onset of HCC in patients with each genotype.
Frequencies of TT, TG, and GG genotypes were 74.3 % (261/351), 24.8 % (87/351), and 0.9 % (3/351), respectively. The mean ages at onset of HCC for TT, TG, and GG genotypes were 69.9, 67.5 and 66.8, respectively. In multivariate analysis, IL28B minor allele (TG and GG genotypes) was an independent risk factor for younger age at onset of HCC (P = 0.02) in males (P < 0.001) with higher body mass index (BMI; P = 0.009). The IL28B minor allele was also associated with a lower probability of having aspartate aminotransferase-to-platelet ratio index (APRI) > 1.5 (minor vs. major, 46.7 vs. 58.6 %; P = 0.01), lower AST (69.1 vs. 77.7 IU/L, P = 0.02), lower ALT (67.8 vs. 80.9 IU/L, P = 0.002), higher platelet count (12.8 vs. 11.2 x 10(4)/mu L, P = 0.002), and higher prothrombin time (79.3 vs. 75.4 %, P = 0.002).
The IL28B minor allele was associated with lower inflammatory activity and less progressed fibrosis of the liver; however, it constituted a risk factor for younger-age onset of HCC in CHC patients.

DOI： 10.1007/s00535-013-0826-x

The role of microRNAs in hepatocarcinogenesis: current knowledge and future prospects Reviewed

Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Motoko Ohno, Akemi Takata, Chikako Shibata, Kazuhiko Koike

JOURNAL OF GASTROENTEROLOGY 49 ( 2 ) 173 - 184 2014.2

Language：English Publisher：SPRINGER JAPAN KK

MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression post-transcriptionally through complementary base pairing with thousands of messenger RNAs. Although the precise biological functions of individual miRNAs are still unknown, miRNAs are speculated to play important roles in diverse biological processes through fine regulation of their target gene expression. A growing body of data indicates the deregulation of miRNAs during hepatocarcinogenesis. In this review, we summarize recent findings regarding deregulated miRNA expression and their possible target genes in hepatocarcinogenesis, with emphasis on inflammation-related hepatocarcinogenesis. Because miRNA-based strategies are being applied to clinical therapeutics, precise knowledge of miRNA functions is crucial both scientifically and clinically. We discuss the current open questions from these points of view, which must be clarified in the near future.

DOI： 10.1007/s00535-013-0909-8

Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells Reviewed

Shinzo Yamamoto, Keisuke Tateishi, Yotaro Kudo, Keisuke Yamamoto, Takayuki Isagawa, Genta Nagae, Takuma Nakatsuka, Yoshinari Asaoka, Hideaki Ijichi, Yoshihiro Hirata, Motoyuki Otsuka, Tsuneo Ikenoue, Hiroyuki Aburatani, Masao Omata, Kazuhiko Koike

CARCINOGENESIS 34 ( 10 ) 2380 - 2388 2013.10

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

Alterations in genes coding for histone modifiers are found in human cancers, suggesting that histone modification is involved in malignant features of neoplastic cells. This study showed that a histone demethylase KDM4C is significant for colonosphere formation by mediating the cross talk between oncogenic pathways through a feed-forward mechanism. The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. We found that the KD of -catenin, an important oncogenic factor in CRC, resulted in not only decreased sphere formation but also impaired upregulation of KDM4C gene in spheres. -Catenin bound to the KDM4C promoter, suggesting that KDM4C is involved in the sphere-forming ability downstream of -catenin in CRC cells. Microarray analysis identified the JAG1 gene that codes for a notch ligand Jagged1 responsible for sphere formation as a target of KDM4C. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation. JAG1 is also a target of -catenin, and chromatin immunoprecipitation analysis showed the binding of -catenin and KDM4C onto the JAG1 promoter during colonosphere formation. Importantly, KDM4C KD ruined the recruitment of -catenin onto the JAG1 promoter independently of the H3-K9 methylation status and blunted JAG1 expression during sphere formation. These data indicate that KDM4C maintains the sphere-forming capacity in CRCs by mediating the -catenin-dependent transcription of JAG1 in a feed-forward manner.

DOI： 10.1093/carcin/bgt174

Activation of p38α in T cells regulates the intestinal host defense against attaching and effacing bacterial infections Reviewed

Eun-Jin Shim, Bo-Ram Bang, Seung-Goo Kang, Jianhui Ma, Motoyuki Otsuka, Jiman Kang, Martin Stahl, Jiahuai Han, Changchun Xiao, Bruce A. Vallance, Young Jun Kang

Journal of Immunology 191 ( 5 ) 2764 - 2770 2013.9

Language：English Publishing type：Research paper (scientific journal) Publisher：5

Intestinal infections by attaching and effacing (A/E) bacterial pathogens cause severe colitis and bloody diarrhea. Although p38α in intestinal epithelial cells (IEC) plays an important role in promoting protection against A/E bacteria by regulating T cell recruitment, its impact on immune responses remains unclear. In this study, we show that activation of p38α in T cells is critical for the clearance of the A/E pathogen Citrobacter rodentium. Mice deficient of p38α in T cells, but not in macrophages or dendritic cells, were impaired in clearing C. rodentium. Expression of inflammatory cytokines such as IFN-γ by p38α-deficient T cells was reduced, which further reduced the expression of inflammatory cytokines, chemokines, and antimicrobial peptide by IECs and led to reduced infiltration of T cells into the infected colon. Administration of IFN-γ activated the mucosal immunity to C. rodentium infection by increasing the expression of inflammation genes and the recruitment of T cells to the site of infection. Thus, p38α contributes to host defense against A/E pathogen infection by regulating the expression of inflammatory cytokines that activate host defense pathways in IECs. Copyright © 2013 by The American Association of Immunologists, Inc.

DOI： 10.4049/jimmunol.1300908

Unique Haploinsufficient Role of the MicroRNA-Processing Molecule Dicer1 in a Murine Colitis-Associated Tumorigenesis Model Reviewed

Takeshi Yoshikawa, Motoyuki Otsuka, Takahiro Kishikawa, Akemi Takata, Motoko Ohno, Chikako Shibata, Young Jun Kang, Haruhiko Yoshida, Kazuhiko Koike

PLOS ONE 8 ( 9 ) e71969 2013.9

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

A widespread downregulated expression of microRNAs (miRNAs) is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and - suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.

DOI： 10.1371/journal.pone.0071969

Inhibition of microRNA122 decreases SREBP1 expression by modulating suppressor of cytokine signaling 3 expression Reviewed

Chikako Shibata, Takahiro Kishikawa, Motoyuki Otsuka, Motoko Ohno, Takeshi Yoshikawa, Akemi Takata, Haruhiko Yoshida, Kazuhiko Koike

Biochemical and Biophysical Research Communications 438 ( 1 ) 230 - 235 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：1

While inhibition of microRNA122 (miR122) function in vivo results in reduced serum cholesterol and fatty acid levels, the molecular mechanisms underlying the link between miR122 function and lipid metabolism remains unclear. Because the expression of SREBP1, a central transcription factor involved in lipid metabolism, is known to be increased by suppressor of cytokine signaling 3 (SOCS3) expression, and because we previously found that SOCS3 expression is regulated by miR122, in this study, we examined the correlation between miR122 status and the expression levels of SOCS3 and SREBP1. SREBP1 expression decreased when SOCS3 expression was reduced by miR122 silencing in vitro. Conversely, SREBP1 expression in miR122-silenced cells was restored by enforced expression of SOCS3. Such correlations were observed in human liver tissues with different miR122 expression levels. These signaling links may explain one of the molecular mechanisms linking inhibition of miR122 function or decreased expression of miR122 to decreased fatty acid and cholesterol levels, in the inhibition of miR122 function, or in pathological status in chronic liver diseases. © 2013 Elsevier Inc.

DOI： 10.1016/j.bbrc.2013.07.064

The flavonoid apigenin improves glucose tolerance through inhibition of microRNA maturation in miRNA103 transgenic mice Reviewed

Motoko Ohno, Chikako Shibata, Takahiro Kishikawa, Takeshi Yoshikawa, Akemi Takata, Kentaro Kojima, Masao Akanuma, Young Jun Kang, Haruhiko Yoshida, Motoyuki Otsuka, Kazuhiko Koike

SCIENTIFIC REPORTS 3 2553 2013.8

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

Polyphenols are representative bioactive substances with diverse biological effects. Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function. The effects were mediated by impaired maturation of a subset of miRNAs, probably through inhibition of the phosphorylation of TRBP, a component of miRNA-generating complexes via impaired mitogen-activated protein kinase (MAPK) Erk activation. While glucose intolerance was observed in miRNA103 (miR103)-overexpressing transgenic mice, administration of apigenin improved this pathogenic status likely through suppression of matured miR103 expression levels. These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP.

DOI： 10.1038/srep02553

Transdifferentiation of human fibroblasts into hepatocyte-like cells by defined transcriptional factors Reviewed

Tomomi Kogiso, Hikaru Nagahara, Motoyuki Otsuka, Keiko Shiratori, Steven F. Dowdy

HEPATOLOGY INTERNATIONAL 7 ( 3 ) 937 - 944 2013.7

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

Liver transplantation is currently the only curative therapeutic option for end-stage liver cirrhosis. However, due to the limitations of donor liver availability and occasional rejection, it cannot always be successfully applied. In this study, we determined whether fibroblasts can be transdifferentiated into hepatocyte-like cells by transcription factors that initiate and maintain hepatocyte differentiation.
Fibroblasts were transduced with retrovirus vectors carrying FOXA2, HNF4 alpha, and C/EBP beta. To enhance the efficiency of transdifferentiation, cMyc was also expressed.
Transdifferentiation was successful using both neonatal fibroblasts and human forehead fibroblasts. The transdifferentiated cells produced hepatocyte-specific proteins such as albumin and cytochrome, and had important hepatocyte-specific functions, such as glycogen storage and indocyanine green uptake, suggesting that the cells function at least as partial hepatocytes.
These results provide a novel method of generating differentiated hepatocyte-like cells, and may represent an alternative source of cells for future cell-based therapeutics for end-stage liver diseases.

DOI： 10.1007/s12072-013-9432-5

A genome-wide association study of HCV-induced liver cirrhosis in the Japanese population identifies novel susceptibility loci at the MHC region Reviewed

Yuji Urabe, Hidenori Ochi, Naoya Kato, Vinod Kumar, Atsushi Takahashi, Ryosuke Muroyama, Naoya Hosono, Motoyuki Otsuka, Ryosuke Tateishi, Paulisally Hau Yi Lo, Chizu Tanikawa, Masao Omata, Kazuhiko Koike, Daiki Miki, Hiromi Abe, Naoyuki Kamatani, Joji Toyota, Hiromitsu Kumada, Michiaki Kubo, Kazuaki Chayama, Yusuke Nakamura, Koichi Matsuda

Journal of Hepatology 58 ( 5 ) 875 - 882 2013.5

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

Background &amp
Aims: We performed a genome-wide association study (GWAS) of hepatitis C virus (HCV)-induced liver cirrhosis (LC) to identify predictive biomarkers for the risk of LC in patients with chronic hepatitis C (CHC). Methods: A total of 682 HCV-induced LC cases and 1045 CHC patients of Japanese origin were genotyped by Illumina Human Hap 610-Quad bead Chip. Results: Eight SNPs which showed possible associations (p &lt
1.0 × 10-5) at the GWAS stage were further genotyped using 936 LC cases and 3809 CHC patients. We found that two SNPs within the major histocompatibility complex (MHC) region on chromosome 6p21, rs910049 and rs3135363, were significantly associated with the progression from CHC to LC (pcombined = 9.15 × 10 -11 and 1.45 × 10-10, odds ratio (OR) = 1.46 and 1.37, respectively). We also found that HLA-DQA1*0601 and HLA-DRB1*0405 were associated with the progression from CHC to LC (p = 4.53 × 10-4 and 1.54 × 10-4 with OR = 2.80 and 1.45, respectively). Multiple logistic regression analysis revealed that rs3135363, rs910049, and HLA-DQA1*0601 were independently associated with the risk of HCV-induced LC. In addition, individuals with four or more risk alleles for these three loci have a 2.83-fold higher risk for LC than those with no risk allele, indicating the cumulative effects of these variations. Conclusions: Our findings elucidated the crucial roles of multiple genetic variations within the MHC region as prognostic/predictive biomarkers for CHC patients. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2012.12.024

MicroRNA-140 acts as a liver tumor suppressor by controlling NF-kappa B activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression Reviewed

Akemi Takata, Motoyuki Otsuka, Takeshi Yoshikawa, Takahiro Kishikawa, Yohko Hikiba, Shuntaro Obi, Tadashi Goto, Young Jun Kang, Shin Maeda, Haruhiko Yoshida, Masao Omata, Hiroshi Asahara, Kazuhiko Koike

HEPATOLOGY 57 ( 1 ) 162 - 170 2013.1

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

MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced nuclear factor-?B (NF-?B) activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF-?B activity by preferentially regulating the function of the NF-?B-suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. DNA methyltransferase 1 (Dnmt1) was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-?B activity. MiRNA-140-knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency-related pathogenesis. Conclusion: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis. (HEPATOLOGY 2013; 57: 162-170)

DOI： 10.1002/hep.26011

MicroRNA-140 acts as a liver tumor suppressor by controlling NF-κB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression. International journal

Akemi Takata, Motoyuki Otsuka, Takeshi Yoshikawa, Takahiro Kishikawa, Yohko Hikiba, Shuntaro Obi, Tadashi Goto, Young Jun Kang, Shin Maeda, Haruhiko Yoshida, Masao Omata, Hiroshi Asahara, Kazuhiko Koike

Hepatology (Baltimore, Md.) 57 ( 1 ) 162 - 70 2013.1

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

UNLABELLED: MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced nuclear factor-κB (NF-κB) activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF-κB activity by preferentially regulating the function of the NF-κB-suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. DNA methyltransferase 1 (Dnmt1) was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-κB activity. MiRNA-140-knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency-related pathogenesis. CONCLUSION: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis.

DOI： 10.1002/hep.26011

Current status of miRNA-targeting therapeutics and preclinical studies against gastroenterological carcinoma. Reviewed

Shibata C, Otsuka M, Kishikawa T, Yoshikawa T, Ohno M, Takata A, Koike K

Molecular and cellular therapies 1 5 2013

Regulation of the expression of the liver cancer susceptibility gene MICA by microRNAs Reviewed

Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Akemi Takata, Chikako Shibata, Yuji Kondo, Masao Akanuma, Haruhiko Yoshida, Kazuhiko Koike

Scientific Reports 3 2739 2013

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

Hepatocellular carcinoma (HCC) is a threat to public health worldwide. We previously identified the association of a single nucleotide polymorphism (SNP) at the promoter region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of hepatitis-virus-related HCC. Because this SNP affects MICA expression levels, regulating MICA expression levels may be important in the prevention of HCC. We herein show that the microRNA (miR) 25-93-106b cluster can modulate MICA levels in HCC cells. Overexpression of the miR 25-93-106b cluster significantly suppressed MICA expression. Conversely, silencing of this miR cluster enhanced MICA expression in cells that express substantial amounts of MICA. The changes in MICA expression levels by the miR25-93-106b cluster were biologically significant in an NKG2D-binding assay and an in vivo cell-killing model. These data suggest that the modulation of MICA expression levels by miRNAs may be a useful method to regulate HCCs during hepatitis viral infection.

DOI： 10.1038/srep02739

A genome-wide association study of HCV-induced liver cirrhosis in the Japanese population identifies novel susceptibility loci at the MHC region Reviewed International journal

Urabe Y, Ochi H, Kato N, Kumar V, Takahashi A, Muroyama R, Hosono N, Otsuka M, Tateishi R, Lo P. H, Tanikawa C, Omata M, Koike K, Miki D, Abe H, Kamatani N, Toyota J, Kumada H, Kubo M, Chayama K, Nakamura Y, Matsuda K

J Hepatol 58 ( 5 ) 875 - 82 2013

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

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) of hepatitis C virus (HCV)-induced liver cirrhosis (LC) to identify predictive biomarkers for the risk of LC in patients with chronic hepatitis C (CHC). METHODS: A total of 682 HCV-induced LC cases and 1045 CHC patients of Japanese origin were genotyped by Illumina Human Hap 610-Quad bead Chip. RESULTS: Eight SNPs which showed possible associations (p<1.0 × 10(-5)) at the GWAS stage were further genotyped using 936 LC cases and 3809 CHC patients. We found that two SNPs within the major histocompatibility complex (MHC) region on chromosome 6p21, rs910049 and rs3135363, were significantly associated with the progression from CHC to LC (pcombined=9.15 × 10(-11) and 1.45 × 10(-10), odds ratio (OR)=1.46 and 1.37, respectively). We also found that HLA-DQA1(*)0601 and HLA-DRB1(*)0405 were associated with the progression from CHC to LC (p=4.53 × 10(-4) and 1.54 × 10(-4) with OR=2.80 and 1.45, respectively). Multiple logistic regression analysis revealed that rs3135363, rs910049, and HLA-DQA1(*)0601 were independently associated with the risk of HCV-induced LC. In addition, individuals with four or more risk alleles for these three loci have a 2.83-fold higher risk for LC than those with no risk allele, indicating the cumulative effects of these variations. CONCLUSIONS: Our findings elucidated the crucial roles of multiple genetic variations within the MHC region as prognostic/predictive biomarkers for CHC patients.

DOI： 10.1016/j.jhep.2012.12.024

Silencing of microRNA-122 enhances interferon-alpha signaling in the liver through regulating SOCS3 promoter methylation Reviewed

Takeshi Yoshikawa, Akemi Takata, Motoyuki Otsuka, Takahiro Kishikawa, Kentaro Kojima, Haruhiko Yoshida, Kazuhiko Koike

SCIENTIFIC REPORTS 2 637 2012.9

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

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. Although novel drugs against HCV are under development, the current standard therapy consists principally of interferon (IFN). To improve the response to IFN treatment by enhancing interferon-stimulated response element (ISRE)-mediated gene transcription, we screened 75 microRNAs highly expressed in hepatocytes for their ability to modulate ISRE activity. Overexpression of microRNA-122 (miR122) significantly suppressed ISRE activity. Conversely, silencing of miR122 function enhanced IFN-induced ISRE activity, by decreasing expression of suppressor of cytokine signaling 3 (SOCS3). This decrease in SOCS3 level was not mediated by microRNA target gene suppression, but rather by enhanced methylation at SOCS3 gene promoter. Taken together, our data, along with the fact that antisense oligonucleotides of miR122 also directly inhibit HCV replication, suggest that a combination therapy comprising IFN and silencing of miR122 function may be a promising therapeutic option in the near future.

DOI： 10.1038/srep00637

A miRNA machinery component DDX20 controls NF-kappa B via microRNA-140 function Reviewed

Akemi Takata, Motoyuki Otsuka, Takeshi Yoshikawa, Takahiro Kishikawa, Yotaro Kudo, Tadashi Goto, Haruhiko Yoshida, Kazuhiko Koike

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 420 ( 3 ) 564 - 569 2012.4

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

Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide, but the molecular mechanisms in tumorigenesis remain largely unknown. Previously, a DEAD-box protein DDX20, a component of microRNA-containing ribonucleoprotein complexes, was identified as a liver tumor suppressor candidate in an oncogenomics-based in vivo RNAi screen. However, the molecular mechanisms were unknown. Here, we show that deficiency of DDX20 results in the enhancement of NF-kappa B activity, a crucial intracellular signaling pathway closely linked with hepatocarcinogenesis. While DDX20 normally suppresses NF-kappa B activity by regulating NF-kappa B-suppressing miRNA-140 function, this suppressive effect was lost in DDX20-deficient cells. The impairment of miRNA function due to DDX20 deficiency appears to be miRNA species-specific at the point of loading miRNAs into the RNA-induced silencing complex. These results indicate that DDX20 deficiency enhances NF-kappa B activity by impairing the NF-kappa B-suppressive action of microRNAs, and suggest that dysregulation of the microRNA machinery components may also be involved in pathogenesis in various human diseases. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.03.034

Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway Reviewed

Yotaro Kudo, Yasuo Tanaka, Keisuke Tateishi, Keisuke Yamamoto, Shinzo Yamamoto, Dai Mohri, Yoshihiro Isomura, Motoko Seto, Hayato Nakagawa, Yoshinari Asaoka, Motohisa Tada, Miki Ohta, Hideaki Ijichi, Yoshihiro Hirata, Motoyuki Otsuka, Tsuneo Ikenoue, Shin Maeda, Shuichiro Shiina, Haruhiko Yoshida, Osamu Nakajima, Fumihiko Kanai, Masao Omata, Kazuhiko Koike

JOURNAL OF HEPATOLOGY 55 ( 6 ) 1400 - 1408 2011.12

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

Background & Aims: Some clinical findings have suggested that systemic metabolic disorders accelerate in vivo tumor progression. Deregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is implicated in both metabolic dysfunction and carcinogenesis in humans; however, it remains unknown whether the altered metabolic status caused by abnormal activation of the pathway is linked to the protumorigenic effect.
Methods: We established hepatocyte-specific Pik3ca transgenic (Tg) mice harboring N1068fs*4 mutation.
Results: The Tg mice exhibited hepatic steatosis and tumor development. PPAR gamma-dependent lipogenesis was accelerated in the Tg liver, and the abnormal profile of accumulated fatty acid (FA) composition was observed in the tumors of Tg livers. In addition, the Akt/mTOR pathway was highly activated in the tumors, and in turn, the expression of tumor suppressor genes including Pten, Xpo4, and Dlc1 decreased. Interestingly, we found that the suppression of those genes and the enhanced in vitro colony formation were induced in the immortalized hepatocytes by the treatment with oleic acid (OA), which is one of the FAs that accumulated in tumors.
Conclusions: Our data suggest that the unusual FA accumulation has a possible role in promoting in vivo hepato-tumorigenesis under constitutive activation of the PI3K pathway. The Pik3ca Tg mice might help to elucidate molecular mechanisms by which metabolic dysfunction contributes to in vivo tumor progression. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.

DOI： 10.1016/j.jhep.2011.03.025

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