Faculty Profiles - Otsuka Motoyuki

Papers - Otsuka Motoyuki

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Direct differentiation of hepatic cells from human induced pluripotent stem cells using a limited number of cytokines Reviewed

Akemi Takata, Motoyuki Otsuka, Tomomi Kogiso, Kentaro Kojima, Takeshi Yoshikawa, Ryosuke Tateishi, Naoya Kato, Shuichiro Shiina, Haruhiko Yoshida, Masao Omata, Kazuhiko Koike

HEPATOLOGY INTERNATIONAL 5 ( 4 ) 890 - 898 2011.12

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

Purpose Development of improved protocols for differentiating induced pluripotent stem (iPS) cells into hepatic cells is an important step toward their use in the field of hepatology. Specifically, the number of different cytokines should be reduced to limit undesired effects and to reduce the cost of the process. In this report, we describe a simple method for directing human iPS cells to differentiate into hepatic cells using only two cytokines and a short incubation time.
Methods A two-step protocol for differentiating iPS cells into hepatic cells was developed. A high dose of activin A was applied for 3 days to induce definitive endoderm formation. Subsequently, cells were treated with hepatocyte growth factor (HGF) for 5 days to generate hepatic cells. Differentiation was confirmed by immunostaining for differentiation markers. Albumin mRNA levels in differentiated hepatic cells generated using a previously tested three-step protocol that uses activin A, fibroblast growth factor (FGF)/bone morphogenetic protein (BMP), and HGF, and our new protocol were compared to determine the efficiency of differentiation.
Results Our two-step protocol induced the differentiation of iPS cells into hepatic cells and required a shorter differentiation period than the previous three-step protocol. The differentiation efficiencies of the two protocols were comparable and the induced hepatic cells were functional.
Conclusions Developing efficient induction and culture methods to generate more highly matured hepatocytes is essential for regenerative cell-based therapies. Our protocol provides a simple, cost-effective, and time-saving approach for generating hepatic cells from iPS cells.

DOI： 10.1007/s12072-011-9251-5

Receptor for Activated Protein Kinase C: Requirement for Efficient MicroRNA Function and Reduced Expression in Hepatocellular Carcinoma Reviewed

Motoyuki Otsuka, Akemi Takata, Takeshi Yoshikawa, Kentaro Kojima, Takahiro Kishikawa, Chikako Shibata, Mutsuhiro Takekawa, Haruhiko Yoshida, Masao Omata, Kazuhiko Koike

PLOS ONE 6 ( 9 ) 2011.9

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

MicroRNAs (miRNAs) are important regulators of gene expression that control physiological and pathological processes. A global reduction in miRNA abundance and function is a general trait of human cancers, playing a causal role in the transformed phenotype. Here, we sought to newly identify genes involved in the regulation of miRNA function by performing a genetic screen using reporter constructs that measure miRNA function and retrovirus-based random gene disruption. Of the six genes identified, RACK1, which encodes "receptor for activated protein kinase C" (RACK1), was confirmed to be necessary for full miRNA function. RACK1 binds to KH-type splicing regulatory protein (KSRP), a member of the Dicer complex, and is required for the recruitment of mature miRNAs to the RNA-induced silencing complex (RISC). In addition, RACK1 expression was frequently found to be reduced in hepatocellular carcinoma. These findings suggest the involvement of RACK1 in miRNA function and indicate that reduced miRNA function, due to decreased expression of RACK1, may have pathologically relevant roles in liver cancers.

DOI： 10.1371/journal.pone.0024359

MicroRNA-22 and microRNA-140 suppress NF-kappa B activity by regulating the expression of NF-kappa B coactivators Reviewed

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

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 411 ( 4 ) 826 - 831 2011.8

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

Nuclear factor kappa B (NF-kappa B) is a transcription factor that regulates a set of genes that are critical to many biological phenomena, including liver tumorigenesis. To identify microRNAs (miRNAs) that regulate NF-kappa B activity in the liver, we screened 60 miRNAs expressed in hepatocytes for their ability to modulate NF-kappa B activity. We found that miRNA-22 and miRNA-140-3p significantly suppressed NF-kappa B activity by regulating the expression of nuclear receptor coactivator 1 (NCOA1) and nuclear receptor-interacting protein 1 (NRIP1), both of which are NF-kappa B coactivators. Our results provide new information about the roles of miRNAs in the regulation of NF-kappa B activity. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.07.048

HCV関連肝細胞癌患者の高齢化と非硬変肝からの発癌の増加

吉田晴彦, 建石良介, 佐藤雅哉, 三神信太郎, 内野康史, 新野徹, 榎奥健一郎, 後藤絵里子, 中川隼人, 増崎良太, 浅岡良成, 大塚基之, 山敷宣代, 五藤忠, 椎名秀一朗, 小俣政男, 小池和彦

肝臓 52 ( Suppl.1 ) A411 - A411 2011.4

Reduced expression of RAS protein activator like-1 in gastric cancer Reviewed

Motoko Seto, Miki Ohta, Tsuneo Ikenoue, Takafumi Sugimoto, Yoshinari Asaoka, Motohisa Tada, Dai Mohri, Yotaro Kudo, Hideaki Ijichi, Keisuke Tateishi, Motoyuki Otsuka, Yoshihiro Hirata, Shin Maeda, Kazuhiko Koike, Masao Omata

INTERNATIONAL JOURNAL OF CANCER 128 ( 6 ) 1293 - 1302 2011.3

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

RAS signaling is frequently deregulated in human neoplasms. However, RAS mutations have been found in only a small proportion of human gastric cancers, implicating other mechanisms in the activation of RAS signaling in gastric tumorigenesis. We have previously reported that decreased expression of RAS protein activator like-1 (RASAL1), a member of the RAS-GTPase-activating proteins that switch off RAS activity, contributes to colon tumor progression. In our study, we explored the involvement of decreased RASAL1 expression in gastric tumorigenesis. RASAL1 expression was reduced in 6 of 10 gastric cancer cell lines examined by immunoblotting. Knockdown of RASAL1 increased mitogen-activated protein kinase signaling in response to growth factor stimulation, and the forced expression of RASAL1 reduced proliferation of gastric cancer cells. Immunohistochemical analyses in primary gastric tumors showed that RASAL1 expression was reduced in 23 of 48 (48%) of the gastric cancers but in none of the adenomas (0/10). Methylation of the RASAL1 promoter region and loss of heterozygosity (LOH) at the RASAL1 locus were examined to investigate the causes of RASAL1 silencing. All cell lines with reduced RASAL1 had RASAL1 methylation, and two had LOH. In primary gastric cancers, methylation or LOH was detected in 50% (6/12) of those with reduced RASAL1. Furthermore, RASAL1 expression was restored in some cell lines by histone deacetylase inhibitor treatment. Our findings demonstrate that reduced RASAL1 expression, partly due to genetic and epigenetic changes, contributes to gastric carcinogenesis, and also re-emphasize the importance of RAS signaling in gastric cancer development.

DOI： 10.1002/ijc.25459

Epithelial p38 alpha Controls Immune Cell Recruitment in the Colonic Mucosa Reviewed

Young Jun Kang, Motoyuki Otsuka, Arjen van den Berg, Lixin Hong, Zhe Huang, Xiurong Wu, Duan-Wu Zhang, Bruce A. Vallance, Peter S. Tobias, Jiahuai Han

PLOS PATHOGENS 6 ( 6 ) e1000934 2010.6

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

Intestinal epithelial cells (IECs) compose the first barrier against microorganisms in the gastrointestinal tract. Although the NF-kappa B pathway in IECs was recently shown to be essential for epithelial integrity and intestinal immune homeostasis, the roles of other inflammatory signaling pathways in immune responses in IECs are still largely unknown. Here we show that p38 alpha in IECs is critical for chemokine expression, subsequent immune cell recruitment into the intestinal mucosa, and clearance of the infected pathogen. Mice with p38 alpha deletion in IECs suffer from a sustained bacterial burden after inoculation with Citrobacter rodentium. These animals are normal in epithelial integrity and immune cell function, but fail to recruit CD4(+) T cells into colonic mucosal lesions. The expression of chemokines in IECs is impaired, which appears to be responsible for the impaired T cell recruitment. Thus, p38 alpha in IECs contributes to the host immune responses against enteric bacteria by the recruitment of immune cells.

DOI： 10.1371/journal.ppat.1000934

DDX20 deficiency enhances NF-kappa B by impairing NF-kappa B suppressive-microRNA function and leads to hepatocarcinogenesis Reviewed

Takata Akemi, Otsuka Motoyuki, Kudo Yotaro, Kojima Kentaro, Maeda Shin, Tateishi Keisuke, Ikenoue Tsuneo, Ijichi Hideaki, Hirata Yoshihiro, Yoshida Haruhiko, Omata Masao, Koike Kazuhiko

CANCER RESEARCH 70 2010.4

Apoptosis Signal-Regulating Kinase 1 Regulates Colitis and Colitis-Associated Tumorigenesis by the Innate Immune Responses Reviewed

Yoku Hayakawa, Yoshihiro Hirata, Hayato Nakagawa, Kei Sakamoto, Yohko Hikiba, Motoyuki Otsuka, Hideaki Ijichi, Tsuneo Ikenoue, Keisuke Tateishi, Masao Akanuma, Keiji Ogura, Haruhiko Yoshida, Hidenori Ichijo, Masao Omata, Shin Maeda

GASTROENTEROLOGY 138 ( 3 ) 1055 - U334 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

BACKGROUND & AIMS: Mitogen-activated protein kinase (MAPK) signaling pathways regulate multiple cellular functions and are implicated in the pathogenesis of inflammatory bowel disease and colitis-associated cancer (CAC). Apoptosis signal-regulating kinase 1 (ASK1) is a MAPK kinase kinase; little is known about the role of ASK1 in colonic disease. We assessed the involvement of ASK1 in the development of intestinal inflammation and CAC. METHODS: Dextran sodium sulfate (DSS) or Citrobacter rodentium was used to induce colitis in wildtype (WT) and ASK1 knock-out (ASK1(-/-)) mice; CAC was induced by azoxymethane injection followed by repeated intake of DSS by the mice. Primary macrophages were isolated from WT and ASK1(-/-) mice and used to investigate the involvement of ASK1 in innate immune responses. Bone marrow chimeric mice were used to study the contribution of myeloid cells to colitis activity. RESULTS: ASK1 deficiency increased susceptibility to colonic inflammation in both models of colitis. In vitro, ASK1(-/-) macrophages were impaired in their ability to kill bacteria and had increased susceptibility to bacterial-induced apoptosis, because p38 was inactivated. Expression of antiapoptotic genes was greatly reduced in ASK1(-/-) macrophages. WT mice given transplants of ASK1(-/-) mouse-derived bone marrow cells developed more severe DSS-induced colitis than mice with WT-derived bone marrow cells. In the CAC model, ASK1(-/-) mice developed more numerous and larger tumors than WT mice through increased colonic inflammation. CONCLUSIONS: ASK1 controls the development of intestinal inflammation and CAC through the regulation of innate immunity.

DOI： 10.1053/j.gastro.2009.11.015

TNF-alpha stimulation inhibits siRNA-mediated RNA interference through a mechanism involving poly-(A) tail stabilization. Reviewed

Mols J, van den Berg A, Otsuka M, Zheng M, Chen J, Han J

Biochimica et biophysica acta 1779 712 - 719 2008.11

TNF-alpha stimulation inhibits siRNA-mediated RNA interference through a mechanism involving poly-(A) tail stabilization Reviewed

Johann Mols, Arjen van den Berg, Motoyuki Otsuka, Min Zheng, Jianming Chen, Jiahuai Han

BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 1779 ( 11 ) 712 - 719 2008.11

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

The control of mRNA stability is a complex biological process that involves numerous factors, including rnicroRNA (miRNA) and short interfering RNA (siRNA). Here, we show that short interfering RNA (siRNA) and rnicroRNA share some similarities in their response to cellular stress. rniR16 expedites the degradation of mRNAs containing AU-rich elements (ARE) in their 31 untranslated region (UTR). si20 is an siRNA designed to target a non-ARE sequence in the TNF 3'UTR. We found that both si20 and miR16/ARE-mediated degradation of mRNAs can be inhibited by stimulating cells with different stresses. By analyzing TNF-alpha stimulation-mediated stabilization of si20- and miR16-targeted mRNA, we show that this stabilization is not caused by modifying si20 and miR16 loading into Ago2 complexes, or mRNA targeting to Ago2, but by inhibiting mRNA deadenylation. This is the first report showing that a specific siRNA-mediated mRNA degradation can be regulated by inflammatory stimuli, and that deadenylation is involved in this siRNA-mediated mRNA decay. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbagrm.2008.03.007

Potential contribution of tumor suppressor p53 in the host defense against hepatitis C virus Reviewed

Narayan Dharel, Naoya Kato, Ryosuke Muroyama, Hiroyoshi Taniguchi, Motoyuki Otsuka, Yue Wang, Amarsanaa Jazag, Run-Xuan Shao, Jin-Hai Chang, Mark K. Adler, Takao Kawabe, Masao Omata

HEPATOLOGY 47 ( 4 ) 1136 - 1149 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

Infection by hepatitis C virus (HCV) usually results into chronic hepatitis that can ultimately lead to cirrhosis and hepatocellular carcinoma. Type 1 interferons (IFN-alpha/beta) constitute the primary cellular defense against viral infection including HCV. IFN binding to their receptors activates associated Jak1 and Tyk2 kinases, which ultimately leads to phosphorylation and assembly of a signal transducer and activator of transcription protein (STAT)1-STAT2-interferon regulatory factor (IRF)9 trimetric complex called interferon-stimulated gene factor 3 that translocates into the nucleus and binds to the interferon-stimulated response elements (ISRE), leading to transcriptional induction of several antiviral genes, including double-stranded RNA-activated protein kinase (PKR), 2',5'-oligoadenylate synthetase (OAS), and myxovirus resistance protein A (MxA). Understanding the mechanisms of how the virus evades this cellular innate defense and establishes a chronic infection is the key for the development of better therapeutics against HCV infection. Here, we demonstrate that p53 could have a crucial role in the cellular innate defense against HCV. We observed significantly higher levels of HCV RNA replication and viral protein expression in the Huh7 cells when their p53 expressions were knocked down. Moreover, IFN treatment was less effective in inhibiting the HCV RNA replication in the p53-knocked-down (p53kd) Huh? cells. In fact, the activation of the ISRE and the induction of ISGs were significantly attenuated in the p53kd Huh? cells and p53 was found to directly interact with IRF9. Conclusion: These observations underscore the potential contributions of the tumor suppressor p53 in cellular antiviral immunity against HCV with possible therapeutic implications.

DOI： 10.1002/hep.22176

Macrophage deletion of p38 alpha partially impairs lipopolysaccharide-induced cellular activation Reviewed

Young Jun Kang, Jianming Chen, Motoyuki Otsuka, Johann Mols, Shuxun Ren, Yinbin Wang, Jiahuai Han

JOURNAL OF IMMUNOLOGY 180 ( 7 ) 5075 - 5082 2008.4

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

The activation of p38 alpha, a MAPK family member, is associated with macrophage activation by microbial pattern molecules, such as LPS. The requirement of p38 alpha in inflammatory responses has been shown in a number of studies using chemical inhibitors, though the inhibitors also inhibit p38 beta and perhaps some other enzymes. In this study, we used conditional knockout of p38 alpha in macrophages to address the role of p38 alpha in macrophage activation. We found that p38 alpha deficiency causes a significant inhibition in the production of LPS-induced TNF-alpha, IL-12, and IL-18, but it has little or no effect on IL-6 or IFN-beta production. Knockout of p38a in macrophages did not affect LPS-induced activation of the other major signaling pathways (NF-kappa B, Jnk, and Erk), nor did it affect the transcriptional activity of NF-kappa B. It had little inhibitory effect on LPS-induced AP-1 activity, but it significantly inhibited LPS-induced C/EBP-beta and CREB activation, indicating that the role of p38 alpha in cytokine production in macrophages is at least in part through its regulation of C/EBP-beta and CREB activation. In addition, we also confirmed that p38 alpha is important for phagocytosis of bacteria by macrophages. Our in vivo studies with two murine models showed that p38 alpha is involved in sepsis. Collectively, our data demonstrate that p38 alpha is an important player in inflammatory responses.

Calcineurin negatively regulates TLR-Mediated activation pathways Reviewed

Young Jun Kang, Brenda Kusler, Motoyuki Otsuka, Michael Hughes, Nobutaka Suzuki, Shinobu Suzuki, Wen-Chen Yeh, Shizuo Akira, Jiahuai Han, Patricia P. Jones

JOURNAL OF IMMUNOLOGY 179 ( 7 ) 4598 - 4607 2007.10

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

In innate immunity, microbial components stimulate macrophages to produce antimicrobial substances, cytokines, other proinflammatory mediators, and IFNs via TLRs, which trigger signaling pathways activating NF-kappa B, MAPKs, and IFN response factors. We show in this study that, in contrast to its activating role in T cells, in macrophages the protein phosphatase calcineurin negatively regulates NF-kappa B, MAPKs, and IFN response factor activation by inhibiting the TLR-mediated signaling pathways. Evidence for this novel role for calcineurin was provided by the findings that these signaling pathways are activated when calcineurin is inhibited either by the inhibitors cyclosporin A or FK506 or by small interfering RNA-targeting calcineurin, and that activation of these pathways by TLR ligands is inhibited by the overexpression of a constitutively active form of calcineurin. We further found that I kappa B-alpha degradation, MAPK activation, and TNF-alpha production by FK506 were reduced in macrophages from mice deficient in MyD88, Toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF), TLR2, or TLR4, whereas macrophages from TLR3-deficient or TLR9 mutant mice showed the same responses to FK506 as those of wild-type cells. Biochemical studies indicate that calcineurin interacts with MyD88, TRIF, TLR2, and TLR4, but not with TLR3 or TLR9. Collectively, these results suggest that calcineurin negatively regulates TLR-mediated activation pathways in macrophages by inhibiting the adaptor proteins MyD88 and TRIF, and a subset of TLRs.

Interferon-beta is activated by hepatitis C virus NS5B and inhibited by NS4A, NS4B, and NS5A Reviewed

Masaru Moriyama, Naoya Kato, Motoyuki Otsuka, Run-Xuan Shao, Hiroyoshi Taniguchi, Takao Kawabe, Masao Omata

HEPATOLOGY INTERNATIONAL 1 ( 2 ) 302 - 310 2007.6

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

Innate immunity is part of the antiviral response. Interferon (IFN)-beta plays a leading role in this system. To investigate the influence of hepatitis C virus (HCV) on innate immunity, we examined the effect of viral proteins on IFN-beta induction. HepG2 cells were co-transfected with plasmids for seven HCV proteins (core protein, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) and the IFN-beta promoter luciferase. Toll-like receptor (TLR) 3 and Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF) play key roles in dsRNA-mediated activation of interferon regulatory factor (IRF)-3 and IFN-beta; therefore, the participation of TLR3/TRIF in NS5B-mediated IFN induction was examined. Among seven HCV proteins, only NS5B, a viral RNA-dependent RNA polymerase (RdRp), activated the IFN-beta promoter. However, mutant NS5B without RdRp activity or template/primer association did not activate the IFN-beta promoter. Activation of the IFN-beta promoter by NS5B required the positive regulatory domain III, a binding sequence for IRF-3. Moreover, IRF-3 was phosphorylated by NS5B. Both inhibition of TLR3 expression by small interfering RNA and expression of the dominant negative form of TRIF significantly reduced NS5B-induced activation of IFN-beta. Of the six other HCV proteins, NS4A, NS4B, and NS5A efficiently inhibited this activation. HCV NS5B is a potent activator of the host innate immune system, possibly through TLR3/TRIF and synthesis of dsRNA. Meanwhile, NS4A, NS4B, and NS5A block IFN-beta induction by NS5B, which may contribute toward the persistence of this virus.

DOI： 10.1007/s12072-007-9003-8

Gene expressions associated with chemosensitivity in human hepatoma cells Reviewed

Yujin Hoshida, Masaru Moriyama, Motoyuki Otsuka, Naoya Kato, Hiroyoshi Taniguchi, Yasushi Shiratori, Naohiko Seki, Masao Omata

HEPATO-GASTROENTEROLOGY 54 ( 74 ) 489 - 492 2007.3

Language：English Publishing type：Research paper (scientific journal) Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: Only limited patients with hepatoma. benefit from chemotherapy without a clear explanation. We aimed to identify genes associated with chemosensitivity using transcriptional profiles. Methodology: In 8 hepatoma cells (HLE, HLF, Huh7, Hep3B, PLC/PRF/5, SK-Hep1, Huh6, and HepG2) transcriptional profiles were obtained using cDNA microarray including 2,300 genes. Chemosensitivities to 8 anticancer drugs (nimustine, mitomycin C, cisplatin, carboplatin, doxorubicin, epirubicin, mitoxantrone, and 5-fluorouracil) were measured by obtaining 50% growth inhibitory concentrations (GI50) using MTT assay. Genes having drug-specific association with chemosensitivity were selected. Results: Up-regulation of topoisomerase II beta was associated with chemo-resistance, the target of doxorubicin. Platinum-specific resistance was associated with superoxide dismutase 2 expression. Antigen peptide transporter I expression correlated with nimustine and mitoxantrone-specific susceptibility. These results were verified by semi-quantitative RT-PCR. Drug inactivators reported in non-liver cancers such as multidrug transporters and drug metabolizers showed less diversity of chemosensitivity in hepatoma cells. Conclusions: To evaluate these gene expressions may be useful to select anticancer drugs, and possibly to consider new therapeutic target to modify drug action.

Absence of tyrosine kinase mutations in Japanese colorectal cancer patients Reviewed

R-X Shao, N. Kato, L-J Lin, R. Muroyama, M. Moriyama, T. Ikenoue, H. Watabe, M. Otsuka, B. Guleng, M. Ohta, Y. Tanaka, S. Kondo, N. Dharel, J-H Chang, H. Yoshida, T. Kawabe, M. Omata

ONCOGENE 26 ( 14 ) 2133 - 2135 2007.3

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

Tyrosine kinases, which are important regulators of intracellular signal-transduction pathways, have mutated forms that are often associated with oncogenesis and are attractive targets for therapeutic intervention. Recently, systematic mutational analyses of tyrosine kinases revealed that a minimum of 30% of colorectal cancer contain at least one mutation in the tyrosine kinases. To further explore these mutations, we examined all reported mutations of NTRK3, FES, KDR, EPHA3, NTRK2, JAK1, PDGFRA, EPHA7, EPHA8, ERBB4, FGFR1, MLK4 and GUCY2F genes in the 24 colorectal cancer cell lines. Unexpectedly, among 24 colorectal cancer cell lines, only two cell lines (LoVo and CaR1) harbored mutation C1408T (R470C) in MLK4 gene. The mutation rate was extremely low compared to that previously reported. Therefore, we analyzed mutations in 46 colorectal cancer samples resected from the same number of Japanese patients. Surprisingly, none of the 46 samples contained any of the mutations reported. Based on our study, we advise that a more comprehensive tyrosine kinase gene mutation assay is necessary in the future.

DOI： 10.1038/sj.onc.1210007

Nucleotide change of codon 38 in the X gene of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma Reviewed

Ryosuke Muroyama, Naoya Kato, Haruhiko Yoshida, Motoyuki Otsuka, Masaru Moriyama, Yue Wang, Run-Xuan Shao, Narayan Dharel, Yasuo Tanaka, Miki Ohta, Ryosuke Tateishi, Shuichiro Shiina, Masashi Tatsukawa, Kenichi Fukai, Fumio Imazeki, Osamu Yokosuka, Yasushi Shiratori, Masao Omata

JOURNAL OF HEPATOLOGY 45 ( 6 ) 805 - 812 2006.12

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

Background/Aims: The hepatitis B virus (HBV) genotype C is associated with the development of hepatocellular carcinoma (HCC). In addition, the HBV X gene, which encodes the pleiotropic transactivator HBx, has also been associated with the development of HCC. In this study, we investigated whether nucleotide changes in the X gene of genotype C are associated with the development of HCC.
Methods/Results: We sequenced the X gene in age- and sex-matched 39 HBV-infected patients with HCC and 36 HBV-infected patients without HCC. A novel nucleotide change that resulted in a proline to serine substitution at codon 38 in HBx (codon-38 change) was preferentially found in patients with HCC. Then, sera were collected from a new group of age- and sex-matched 52 patients with HCC and 51 patients without HCC. In this cohort also, the codon-38 change was associated with HCC. Multiple logistic regression analysis showed the prevalence of the codon-38 change was significantly associated with HCC in all patients (P = 0.001, odds ratio: 4.89).
Conclusion: The codon-38 change in genotype C is an independent risk factor for the development of HCC and may serve as a useful molecular marker for predicting the clinical outcomes in patients infected with HBV. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2006.07.025

Hepatitis C virus core protein is a potent inhibitor of RNA silencing-based antiviral response Reviewed

Y Wang, N Kato, A Jazag, N Dharel, M Otsuka, H Taniguchi, T Kawabe, M Omata

GASTROENTEROLOGY 130 ( 3 ) 883 - 892 2006.3

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Background & Aims: Persistent infection with hepatitis C virus (HCV) leads to chronic hepatitis and hepatocellular carcinoma (HCC). RNA interference (RNAi) may act as a host antiviral response against viral RNA. Methods: The effects of RNAi on both the replicative intermediates and the internal ribosome entry site (IRES) of HCV were studied by using HCV-related short interfering RNA (siRNA) detection assay. The mechanism that permits HCV to escape RNAi was studied by using RNAi assay materials. Results: These studies demonstrate that the Dicer, an RNase enzyme that generates short siRNA, can target and digest both the IRES and the replicative intermediate of HCV into siRNA of similar to 22 nucleotides. Further studies also show that Dicer can inhibit the replication of the HCV subgenomic replicon. However, the HCV core protein inhibits this RNAi and rescues the replication of the HCV subgenomic replicon through a direct interaction with Dicer. Conclusions: RNAi is a limiting factor for HCV infection, and the core protein suppresses the RNA silencing-based antiviral response. This ability of the core protein to counteract the host defense may lead to a persistent viral infection and may contribute to the pathogenesis of HCV.

DOI： 10.1053/j.gastro.2005.12.028

Identifying genes with differential expression in gemcitabine-resistant pancreatic cancer cells using comprehensive transcriptome analysis Reviewed

Y Nakai, M Otsuka, Y Hoshida, M Tada, Y Komatsu, T Kawabe, M Omata

ONCOLOGY REPORTS 14 ( 5 ) 1263 - 1267 2005.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Pancreatic cancer is often unresectable at diagnosis, and chemotherapy using gemcitabine is now the standard treatment for advanced pancreatic cancer. However, acquired resistance to gemcitabine resulting in therapeutic failure is often encountered. Therefore, we sought to identify genes that determine gemcitabine resistance by evaluating the relationship between gene expression profiles and gemcitabine sensitivity to provide molecular targets for overcoming gemcitabine resistance. First, the gemcitabine concentration needed for 50% growth inhibition was examined in six pancreatic cancer cell lines. By exposing MIA PaCa-2 cells to long-term gemcitabine, we established gemcitabine-resistant cells. The gene expression profiles of the six pancreatic cancer cell lines and gemcitabine-resistant cells were determined using cDNA microarray analysis. By comparing the results, 30 genes were identified as differentially expressed genes correlated with gemcitabine sensitivity. Differentially expressed genes in the parental cell lines were also examined, and six overlapping genes were identified as genes correlated with gemcitabine sensitivity in both assays. Of these genes, the down-regulated expression of TNFSF6 protein, also known as Fas ligand, was confirmed in the gemcitabine-resistant cell line. These results should provide therapeutic molecular targets for overcoming gemcitabine resistance.

Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C Reviewed

N Kato, GJ Ji, Y Wang, M Baba, Y Hoshida, M Otsuka, H Taniguchi, M Moriyama, N Dharel, T Goto, RX Shao, T Matsuura, K Ishii, S Shiina, T Kawabe, M Muramatsu, M Omata

HEPATOLOGY 42 ( 4 ) 846 - 853 2005.10

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRAI, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC.

DOI： 10.1002/hep.20860

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