Faculty Profiles - Otsuka Motoyuki

Papers - Otsuka Motoyuki

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NF-kappa B and ERK-signaling pathways contribute to the gene expression induced by cag PAI-positive-Helicobacter pylori infection Reviewed

Wataru Shibata, Yoshihiro Hirata, Haruhiko Yoshida, Motoyuki Otsuka, Yujin Hoshida, Keiji Ogura, Shin Maeda, Tomoya Ohmae, Ayako Yanai, Yuzo Mitsuno, Naohiko Seki, Takao Kawabe, Masao Omata

WORLD JOURNAL OF GASTROENTEROLOGY 11 ( 39 ) 6134 - 6143 2005.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBL GRP CO LTD

AIM: To elucidate the sequential gene expression profile in AGS cells co-cultured with wild-type Helicobacter pylori (H pylori) as a model of H pylori-infected gastric epithelium, and to further examine the contribution of cag-pathogenicity islands (cagPAI)-coding type IV secretion system and the two pathways, nuclear factor kappa B (NF-kappa B) and extracellular signal-regulated kinases (ERK) on wild-type H pylori-induced gene expression.
METHODS: Gene expression profiles induced by H pylori were evaluated in AGS gastric epithelial cells using cDNA microarray, which were present in the 4 600 independent clones picked up from the human gastric tissue. We also analyzed the contribution of NF-kappa B and ERK signaling on H pylori-induced gene expression by using inhibitors of specific signal pathways. The isogenic mutant with disrupted cagE (Delta cagE) was used to elucidate the role of cagPAI-encoding type IV secretion system in the gene expression profile.
RESULTS: According to the expression profile, the genes were classified into four clusters. Among them, the clusters characterized by continuous upregulation were most conspicuous, and it contained many signal transducer activity-associated genes. The role of cagPAI on cultured cells was also investigated using isogenic mutant cagE, which carries non-functional cagPAI. Then the upregulation of more than 80% of the induced genes (476/566) was found to depend on cagPAI. Signal transducer pathway through NF-kappa B or ERK are the major pathways which are known to be activated by cagPAI-positive H pylori. The role of these pathways in the whole signal activation H pylori was analyzed. The specific inhibitors against NF-kappa B or ERK pathway blocked the activation of gene expression in 65% (367/566) or 76% (429/566) of the genes whose activation appealed to depend on cagPAI.
CONCLUSION: These results suggest that more than half of the genes induced by cagPAI-positive H pylori depend on NF-kappa B and ERK signaling activation, and these pathways may play a role in the gene expression induced by host-bacterial interaction which may associate with H pylori-related gastro-duodenal diseases. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

No mutations in the tyrosine kinases of human hepatic, pancreatic, and gastric cancer cell lines Reviewed

RX Shao, M Otsuka, N Kato, JH Chang, R Muroyama, H Taniguchi, M Moriyama, Y Wang, T Kawabe, M Omata

JOURNAL OF GASTROENTEROLOGY 40 ( 9 ) 918 - 918 2005.9

Hepatitis C virus core protein and hepatitis activity are associated through transactivation of interleukin-8 Reviewed

Y Hoshida, N Kato, H Yoshida, Y Wang, M Tanaka, T Goto, M Otsuka, H Taniguchi, M Moriyama, F Imazeki, O Yokosuka, T Kawabe, Y Shiratori, M Omata

JOURNAL OF INFECTIOUS DISEASES 192 ( 2 ) 266 - 275 2005.7

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

Background. We evaluated the association between variations in hepatitis C virus (HCV) core protein and hepatitis severity in patients with chronic HCV infection who achieved remission without viral eradication and had a biochemical response to interferon (IFN) therapy, to evaluate the effect of HCV core sequence in the absence of the influence of host factors.
Methods. Using serum from 10 patients with a biochemical response and 10 patients with no response, we measured serum levels of interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFN-gamma, and tumor necrosis factor-alpha before and after IFN therapy. Expression vectors with the core region were transfected into Huh7 cells, and cytokine induction was evaluated by reporter assay.
Results. In biochemical responders, only IL-8 levels decreased after IFN therapy (P = .04). Changes in the C-terminal hydrophobic region were observed more frequently in biochemical responders. Activation of the IL-8 promoter by HCV core protein was significantly decreased in biochemical responders after IFN therapy (P = .04). When 69 C-terminal amino acids from before IFN therapy were replaced with those from after IFN therapy in 3 biochemical responders, their ability to transactivate IL-8 decreased.
Conclusions. Differences in amino acids in the HCV core protein correlates with hepatitis activity through the modulation of IL-8 induction in HCV-infected patients.

DOI： 10.1086/430924

Interaction between the HCVNS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses Reviewed

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

HEPATOLOGY 41 ( 5 ) 1004 - 1012 2005.5

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

The persistent nature of hepatitis C virus (HCV) infection suggests that HCV encodes proteins that enable it to overcome host antiviral responses. Toll-like receptor 3 (TLR3)-mediated signaling, which recognizes the double-stranded RNA that is produced during viral replication and induces type I interferons, including interferon beta (IFN-beta), is crucial to the host defense against viruses. Recent studies suggest that a TIR domain-containing adaptor protein, TRIF, and two protein kinases, TANK-binding kinase-1 (TBK1) and I kappa B kinase-epsilon (IKK epsilon), play essential roles in TLR3-mediated IFN-beta production through the activation of the transcriptional factor interferon regulatory factor 3 (IRF-3). We report that the HCV NS3 protein interacts directly with TBK1, and that this binding results in the inhibition of the association between TBK1 and IRF-3, which leads to the inhibition of IRF-3 activation. In conclusion, these results suggest the mechanisms of the inhibition of the innate immune responses of HCV infection by NS3 protein.

DOI： 10.1002/hep.20666

Hepatic gene expression profiles associated with fibrosis progression and hepatocarcinogenesis in hepatitis C patients Reviewed

Run-Xuan Shao, Yujin Hoshida, Motoyuki Otsuka, Naoya Kato, Ryosuke Tateishi, Takuma Teratani, Shuichiro Shiina, Hiroyoshi Taniguchi, Masaru Moriyama, Takao Kawabe, Masao Omata

WORLD JOURNAL OF GASTROENTEROLOGY 11 ( 13 ) 1995 - 1999 2005.4

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBL GRP CO LTD

AIM: To determine fibrosis progression and hepatocellular carcinoma (HCC), using simultaneous gene expression analysis.
METHODS: Total RNA samples were extracted from liver biopsies from 19 patients with hepatitis C virus (HCV) infection and 3 patients without HCV infection. Among the 19 HCV-infected patients, 7 and 12 patients had grade F1-2 and F3-4 fibrosis, respectively. Of the 12 patients with F3-4 fibrosis, 8 had HCC. Gene expression in the liver samples was determined using an oligonucleotide microarray. The following comparisons were performed: normal livers vs HCV-infected livers; F1-2 vs F3-4; and F3-4 with HCC vs F3-4 without HCC. Genes that were differentially expressed between these groups were identified based on signal-to-noise ratios.
RESULTS: In the HCV-infected livers, genes involved in immune responses were highly expressed. Expression levels of genes for plasma proteins and drug-metabolizing enzymes were decreased and those of genes involved in the cell cycle and oncogenesis were increased in the F3-4 cases as compared to the F1-2 cases. Among the F3-4 cases, genes involved in carbohydrate metabolism tended to be more highly expressed in patients with HCC than in patients without HCC.
CONCLUSION: We identified genes that are associated with fibrosis progression and hepatocarcinogenesis. This information may be used to detect increased carcinogenic potential in the livers of patients with HCV infection. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

Vitamin K2 binds 17 beta-hydroxysteroid dehydrogenase 4 and modulates estrogen metabolism Reviewed

M Otsuka, N Kato, T Ichimura, S Abe, Y Tanaka, H Taniguchi, Y Hoshida, M Moriyama, Y Wang, RX Shao, D Narayan, R Muroyama, F Kanai, T Kawabe, T Isobe, M Omata

LIFE SCIENCES 76 ( 21 ) 2473 - 2482 2005.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Vitamin K is a cofactor for gamma-glutamyl carboxylase, an enzyme that is important for blood coagulation. Recent studies have shown that vitamin K has other roles, in addition to post-transcriptional modification, such as bone metabolism and antitumoral actions; these findings have indicated that there might be unknown intracellular binding proteins that are specific for vitamin K. In this study, vitamin K-binding proteins were characterized by pull-down experiment using a chemically synthesized biotynylated vitamin K followed by mass spectrometric identification of the pull-downed components. The results indicated that 17 beta hydroxy steroid dehydrogenase 4, apolipoportein E, and 40S ribosomal proteins S7 and S13 might be the candidates of the vitamin K-binding proteins. Subsequent experiments showed that vitamin K2 binds 17 beta hydroxysteroid dehydrogenase 4 and decreases the intracellular estradiol:estrone ratio, which resulted in the inhibition of the amount of estrogen receptor alpha-binding to its target DNA. These results suggest a. possible novel role for vitamin K in modulating estrogen function. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2004.12.020

Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways Reviewed

RX Shao, M Otsuka, N Kato, H Taniguchi, Y Hoshida, M Moriyama, T Kawabe, M Omata

GASTROENTEROLOGY 128 ( 1 ) 86 - 95 2005.1

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

Background& Aims: Hepatocellular carcinoma (HCC) is one of the most common human malignancies. Its high mortality rate is mainly a result of high intrahepatic recurrence. The novel synthetic retinoid acyclic retinoid (ACR) has been reported to prevent the recurrence of human HCC after surgical resection of primary tumors, but the molecular mechanisms underlying its effects remain to be elucidated. In this study, we clarified the molecular targets of ACR. Methods: The inhibitory effects by ACR on growth were examined. Intracellular signaling induced by ACR was comprehensively studied by a reporter assay. Gene expression changes by ACR were examined using a microarray. From these results, a candidate signaling pathway modulated by ACR was determined and whether antagonizing this pathway reverses the effect was examined. Results: We show that ACR inhibits the growth of HCC cells through the down-regulation of fibroblast growth factor (FGF) receptor 3 expression and FGF-mediated signaling, which in turn suppresses the activity of Rho and serum response factor-mediated transcription. Conversely, overexpression of the active form of FGF receptor 3 or the addition of FGF reverses the ACR-mediated inhibition of growth. In addition, silencing the FGF receptor 3 gene by RNA interference inhibits cell growth. Conclusions: These studies show that ACR is a potent inhibitor of FGF signaling and that selective blocking of the FGFmediated pathway could be a promising therapeutic approach for the management of patients with HCC.

DOI： 10.1053/j.gastro.2004.09.077

A simple combination of serum type IV collagen and prothrombin time to diagnose cirrhosis in patients with chronic active hepatitis C Reviewed

Y Qiu, YJ Hoshida, N Kato, M Moriyama, M Otsuka, H Taniguchi, T Kawabe, M Omata

HEPATOLOGY RESEARCH 30 ( 4 ) 214 - 220 2004.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

Background/aim: Cirrhosis in chronic hepatitis C is a major cause of mortality. The components of reported diagnostic indices of cirrhosis based on biochemical markers may be modified by therapies for hepatic inflammation. We aimed to construct index of cirrhosis in patients treated for chronic active hepatitis.
Methods: Using sera of consecutive 140 patients with chronic hepatitis C, routine blood tests including fibrosis markers, type IV collagen and procollagen type III peptide (PIIIP), were performed. Diagnosis of cirrhosis was determined by biopsy. Using multivariate analyses, diagnostic indices of cirrhosis were constructed.
Results: Fifty-eight patients were diagnosed to have cirrhosis. Platelet count, prothrombin time, and albumin were lower, and type IV collagen and PIIIP were higher in patients with cirrhosis (p < 0.05). There was no difference in aspartate and alanine aminotransferases (AST, ALT) and gamma-glutamyl-transpeptidase (GGT) (p > 0.3). Our diagnostic indices I (prothrombin time and platelet count) and II (prothrombin time and type IV collagen) of cirrhosis showed the area under the ROC curves (AUC) of 0.77 and 0.81, respectively. The index II was relatively superior to the index I.
Conclusions: Using combination of type IV collagen and prothrombin time, efficient diagnosis of cirrhosis can be performed in patients with chronic active hepatitis C. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.hepres.2004.10.006

Genes associated with human hepatocellular carcinoma cell chemosensitivity to 5-fluorouracil plus interferon-alpha combination chemotherapy Reviewed

M Moriyama, Y Hoshida, N Kato, M Otsuka, H Yoshida, T Kawabe, M Omata

INTERNATIONAL JOURNAL OF ONCOLOGY 25 ( 5 ) 1279 - 1287 2004.11

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

Recently, combined chemotherapy with 5-fluorouracil (5-FU) and interferon (IFN)-alpha has been reported to show marked effects in patients with advanced hepatocellular carcinoma. We investigated the genes associated with susceptibility to this combination therapy. The gene expression profiles of eight human hepatocellular carcinoma cells (HepG2, Hep3B, Huh7, Huh6, PLC/PRF/5, HLE, HLF, and SK-Hep1) were evaluated using an oligonucleotide microarray that consisted of 3,800 genes. The 50% growth inhibitory concentration (GI50) values for 5-FU, IFN-alpha, and the combination of 5-FU plus IFN-a were determined by the MTT assay. We selected genes that were expressed differentially between the cells with increased susceptibility to the combination therapy and the remaining cells. Relevance networks of the gene expression patterns and GI50 values of the susceptible cells were constructed to find genes associated with susceptibility to the combination therapy. Of the eight cells tested, five showed increased susceptibility to 5-FU plus IFN-alpha compared with 5-FU treatment alone. Among the 3,800 genes, 25 were expressed differentially between susceptible cells and resistant cells. The relevance networks revealed that sensitivity to 5-FU plus IFN-a involved the expression of 27 independent genes, which included 10 genes that are commonly associated with sensitivity to 5-FU alone. We selected a set of genes to predict susceptibility to 5-FU plus IFN-alpha combination therapy. We also selected genes that play key roles in the synergistic effect of this combination therapy. These gene sets should prove useful in evaluations of the efficacy and underlying molecular mechanisms of this combination therapy.

Vitamin K-2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation Reviewed

M Otsuka, N Kato, RX Shao, Y Hoshida, H Ijichi, Y Koike, H Taniguchi, M Moriyama, Y Shiratori, T Kawabe, M Omata

HEPATOLOGY 40 ( 1 ) 243 - 251 2004.7

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

Hepatocellular carcinoma (HCC) is a common human malignancy. Its high mortality rate is mainly a result of high intrahepatic recurrence and portal venous invasion (PVI). We previously reported that the development of PVI is related to levels of des-gamma-carboxy prothrombin (DCP), a serum protein that increases at a notably higher rate in patients with HCC. Because DCP is produced by a vitamin K shortage, we examined the biological effects of extrinsic supplementation of vitamin K-2 in HCC cells in vitro and in vivo. Consequently, vitamin K-2 inhibits the growth and invasion of HCC cells through the activation of protein kinase A, which modulates the activities of several transcriptional factors and inhibits the small GTPase Rho, independent of suppression of DCP. In addition, administration of vitamin K-2 to nude mice inoculated with liver tumor cells reduced both tumor growth and body weight loss. In conclusion, similar to an acyclic retinoid-which was previously reported to prevent the recurrence of HCC-vitamin K-2, another lipid-soluble vitamin, may be a promising therapeutic means for the management of HCC.

DOI： 10.1002/hep.20260

UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma in Japanese patients with hepatitis C virus infection Reviewed

Y Wang, N Kato, Y Hoshida, M Otsuka, H Taniguchi, M Moriyama, S Shiina, T Kawabe, YM Ito, M Omata

CLINICAL CANCER RESEARCH 10 ( 7 ) 2441 - 2446 2004.4

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

Purpose: Genetic polymorphisms of UDP-glucuronosyl-transferase 1A7 (UGT1A7), which detoxifies endogenous and environmental carcinogens, have been reported to be associated with hepatocellular carcinoma (HCC) in German populations. On the other hand, we reported that interleukin-1beta (IL-1beta) gene polymorphisms were associated with hepatitis C virus (HCV)-related HCC. In this study, we evaluated the association of both genes with the risk of HCC in Japanese HCV-infected patients.
Experimental Design: Genetic polymorphisms of UGT1A7 and IL-1beta were investigated in 280 Japanese patients (122 with HCC and 158 without HCC) with chronic HCV infections, by use of standard PCR-based genotyping techniques.
Results: We designated the UGT1A7*1 allele (a haplotype conferring higher activity) as H and the *2, *3, and *4 alleles (haplotypes conferring lower activity) as L. The proportions of UGT1A7 L/L and H/L alleles (genotypes) in patients with HCC (25% and 45%, respectively) were higher than those in patients without HCC (15% and 39%, respectively) with odds ratios of 2.73 (95% confidence interval, 1.40-5.35) and 1.80 (95% confidence interval, 1.05-3.09), respectively, compared with the UGT1A7 H/H alleles. Multivariate analyses revealed that UGT1A7 L/L and IL-1beta/-31T/T-511C/C genotypes, the presence of cirrhosis, age 60 years, male sex, and alpha-fetoprotein >20 mug/ml were associated with the presence of HCC (odds ratios, 2.33, 2.67, 4.20, 3.12, 3.09, and 2.90, respectively).
Conclusion: The UGT1A7 polymorphisms together with IL-1beta were associated with the presence of HCC in Japanese HCV-infected patients.

DOI： 10.1158/1078-0432.CCR-1187-3

Smad4-independent regulation of p21/WAF1 by transforming growth factor-beta Reviewed

H Ijichi, M Otsuka, K Tateishi, T Ikenoue, T Kawakami, F Kanai, Y Arakawa, N Seki, K Shimizu, K Miyazono, T Kawabe, M Omata

ONCOGENE 23 ( 5 ) 1043 - 1051 2004.2

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

The transforming growth factor-beta (TGF-beta)-Smad signaling pathway inhibits the growth of human epithelial cells and plays a role in tumor suppression. The Smad4 gene is mutated or deleted in 50% of pancreatic cancers. In this study, the Smad4-null pancreatic cancer cell line BxPC-3 was transfected with either the Smad4 expression vector or the empty vector and incubated in the presence or absence of TGF-beta. The cells were analysed using a cDNA microarray, which included 2280 named genes to screen for target genes regulated by TGF-beta in either a Smad4-dependent or -independent manner. The microarray and subsequent quantitative RT-PCR analysis demonstrated that the Smad4-independent and -dependent signaling pathways driven by TGF-beta upregulated only one of the 2280 genes, respectively, suggesting that Smad4-independent signaling downstream of TGF-beta might be as widespread as Smad4-dependent signaling. In this study, we demonstrated that the cyclin-dependent kinase inhibitor p21/WAF1, which has been considered the major effector of the Smad-dependent growth inhibitory signal of TGF-beta, is upregulated in a Smad4-independent manner. The upregulation occurs through Smad2/3-dependent transcriptional activation of the p21/WAF1 promoter region. These results suggest a novel mechanism of gene regulation, that is, a novel signal mediator other than Smad4.

DOI： 10.1038/sj.onc.1207222

Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription Reviewed

H Taniguchi, N Kato, M Otsuka, T Goto, H Yoshida, Y Shiratori, M Omata

JOURNAL OF MEDICAL VIROLOGY 72 ( 1 ) 52 - 59 2004.1

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

The majority of persons with chronic hepatitis C virus (HCV) infection develop liver fibrosis. Transforming growth factor (TGF)-beta1 plays a pivotal role in the pathogenesis of post-inflammatory liver scarring. To clarify the influence of HCV infection on liver fibrosis, a reporter assay was used to investigate the effect of viral proteins on TGF-beta1 expression in human hepatoma cells. Of all HCV proteins investigated (core, E1/E2/p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), only the core protein activated the TGF-beta1 promoter and upregulated TGF-beta1 expression measured by an RNase protection assay. Bases -376 to -331 by in the promoter region of TGF-beta1 are responsible for upregulation by HCV core protein, and the nuclear protein that binds to this region increased with the stimulation of HCV core protein. Blocking the mitogen-activated protein kinase pathway prevented upregulation of TGF-beta1 by HCV core protein. The immunological response is supposed to be a major factor to cause the secretion of TGF-beta1 from non-parenchymal cells, but the results suggest that the HCV core protein expression may upregulate directly TGF-beta1 transcription in parenchymal cells and suggest a new paradigm for exacerbation of liver fibrosis by HCV infection.

DOI： 10.1002/jmv.10545

Antiapoptotic regulation by hepatitis C virus core protein through up-regulation of inhibitor of caspase-activated DNase Reviewed

R Sacco, T Tsutsumi, R Suzuki, M Otsuka, H Aizaki, S Sakamoto, M Matsuda, N Seki, Y Matsuura, T Miyamura, T Suzuki

VIROLOGY 317 ( 1 ) 24 - 35 2003.12

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

The hepatitis C virus (HCV) core protein is considered to influence multiple cellular processes. We developed a human hepatoblastoma HepG2-derived inducible cell line, Hep191, which allows tightly regulated expression of the core protein at relatively low but physiological levels under control of the ecdysone-regulated promoter. By transcriptional profiling, we identified differentially expressed genes, some of which are involved in cell growth or apoptosis such as inhibitor of caspase-activated DNase (ICAD), defender against cell death 1, tumor necrosis factor (TNF) receptor 1, and cytochrome c oxidase subunit VIII. Furthermore, we found that core protein expression increases a steady-state level of ICAD protein, possibly through enhancing its promoter activity, and inhibits caspase-3 activity induced by anti-Fas antibody. Since Fas- or TNF-mediated DNA fragmentation is suppressed in the core-induced Hep191 cells, these findings suggest that expression of HCV core at physiological levels confers blocking activity of caspase-activated DNase and consequently inhibiting apoptotic cell death. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.virol.2003.08.028

Comparing gene expression profiles in human liver, gastric, and pancreatic tissues using full-length-enriched cDNA libraries Reviewed

M Otsuka, M Arai, M Mori, M Kato, N Kato, O Yokosuka, T Ochiai, M Takiguchi, M Omata, N Seki

HEPATOLOGY RESEARCH 27 ( 1 ) 76 - 82 2003.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

In the post-genome-sequencing era, full-length cDNA-sequence resources are extremely useful for functional analyses of genes. In addition, comprehensive gene profiling of human tissues at the mRNA level is also useful in understanding the molecular mechanisms of tissue-specific functions and disease pathogenesis. In this study, to obtain a wide variety of full-length cDNA clones derived from digestive tissues, numerous expressed sequence tags were generated from libraries enriched with full-length cDNAs. In total, 13 575 sequences were obtained from three cDNA libraries, which were constructed from tissues and cell lines of human liver, stomach, and pancreas. The integration of overlapping clones categorized the sequences into 5936 clusters (1666, 2746, and 2222 clusters in the liver, stomach, and pancreas, respectively). Of these, 1138 clones were scored as full-length cDNAs. Surprisingly, the redundant clones from all three tissues were assembled to show that only 101 genes (1.7% of the assembled 5936 genes) were shared. These results suggest that functional differences between tissues are probably related to their divergent gene expression profiles, and form a basis for understanding the molecular mechanisms underlying tissue-specific pathogenesis that are expressed in different organs. In addition, the full-length cDNAs obtained in this study should prove useful for future functional analyses of the genes expressed in digestive tissues. (C) 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/S1386-6346(03)0161-X

肝細胞癌患者血清のプロテオミクス解析 Reviewed

星田有人, 川上高幸, 大塚基之, 谷口寿章, 西村信一郎, 小尾俊太郎, 椎名秀一朗, 川邊隆夫, 小俣政男

肝臓 44 ( Suppl.1 ) A174 - A174 2003.4

Liver chip and gene shaving Reviewed

M Otsuka, Y Hoshida, N Kato, M Moriyama, H Taniguchi, M Arai, M Mori, N Seki, M Omata

JOURNAL OF GASTROENTEROLOGY 38 89 - 92 2003.3

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

A comprehensive profile of genes expressed at the mRNA level in various human tissues is considered to be important for understanding the molecular mechanisms of the tissue-specific function and the pathogenesis of related diseases. Here, the gene expression profiling in three human digestive tissues, liver, stomach, and pancreas, was catalogued by generating a large number of expressed sequence tags, and clarified how quantitatively the gene expressions are different. After assembling the redundant clones among three tissues, the results showed that only 1.7% among the assembled genes was expressed commonly in the investigated tissues. These results suggest that the significant functional divergences in different tissues must be related to the divergence of the gene expression profiles. Recently, microarray technologies are widely used. Considering the results that different genes express in different tissues, however, it is important to spot the cDNAs derived from the same tissues or cells examined to acquire information efficiently. For the study of digestive diseases, we constructed an in-house microarray by using the cDNA sets derived from the digestive tissues (liver and gastric chip). In addition, because the amount of information acquired by the microarray analyses is huge, the power of bioinformatics for unifying the obtained data is indispensable. Some examples of the strategies for handling the microarray data obtained by our in-house microarrays are shown in this article.

Synergistic activation of the serum response element-dependent pathway by hepatitis B virus X protein and large-isoform hepatitis delta antigen Reviewed

T Goto, N Kato, H Yoshida, M Otsuka, M Moriyama, Y Shiratori, K Koike, M Matsumura, M Omata

JOURNAL OF INFECTIOUS DISEASES 187 ( 5 ) 820 - 828 2003.3

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

Hepatitis delta virus (HDV) is a naturally occurring satellite of hepatitis B virus (HBV). There are few studies of the effects of the combination of HBV and HDV proteins (HDV antigens [HDAgs]) on intracellular signaling pathways. To understand the influence of HBV and HDV coinfection on hepatocytes, we investigated the effect of HBV proteins and HDAgs on the serum response element (SRE)-dependent pathway. Reporter assays revealed that only HBV X protein (HBx), alone or with the large isoform of HDAg (LHDAg), synergistically activated the SRE-dependent pathway. The effect of HBx and LHDAg on Elk1 or serum response factor (SRF) was examined, because both proteins bind to the SRE. HBx activated the transcriptional ability of Elk1, whereas LHDAg activated the transcriptional ability of SRF. Thus, HBx and LHDAg synergistically activated the SRE-dependent pathway. These results may help us understand clinical phenomena in patients coinfected with HBV and HDV.

DOI： 10.1086/368389

Study of digestive diseases in post-genome era Reviewed

Masao Omata, Motoyuki Otsuka, Takayuki Kawakami, Yujin Hoshida

Japanese Journal of Gastroenterology 100 ( 2 ) 135 - 143 2003.2

Relevance network between chemosensitivity and transcriptome in human hepatoma cells Reviewed

M Moriyama, Y Hoshida, M Otsuka, S Nishimura, N Kato, T Goto, H Taniguchi, Y Shiratori, N Seki, M Omata

MOLECULAR CANCER THERAPEUTICS 2 ( 2 ) 199 - 205 2003.2

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

Generally, hepatoma is not a chemosensitive tumor, and the mechanism of resistance to anticancer drugs is not fully elucidated. We aimed to comprehensively evaluate the relationship between chemosensitivity and gene expression profile in human hepatoma cells, by using microarray analysis, and analyze the data by constructing relevance networks.
In eight hepatoma cell lines (HLE, HLF, Huh7, Hep3B, PLC/PRF/5, SK-Hep1, Huh6, and HepG2), the baseline expression levels of 2300 genes were measured by cDNA microarray. The concentrations of eight anticancer drugs (nimustine, mitomycin C, cisplatin, carboplatin, doxorubicin, epirubicin, mitoxantrone, and 5-fluorouracil) needed for 50% growth inhibition were examined and used as a measure of chemosensitivity. These data were combined and comprehensive pair-wise correlations between gene expression levels and the 50% growth inhibition values were calculated. Significant correlations with significance were used to construct networks of similarity.
Fifty-two relations, including 42 genes, were selected. Among them, nearly 20% were various types of transporters, and most of them negatively correlated with chemosensitivity. Transporter associated with antigen processing 1 was associated with resistance to mitoxantrone, consistent with previous reports. Other transporters were not reported previously to associate with chemosensitivity. Resistance to doxorubicin and its analogue, epirubicin, were positively correlated with topoisomerase II beta expression, whereas it negatively correlated with expression of carboxypeptidases A3 and Z. Response to nimustine was associated with expression of superoxide dismutase 2.
Relevance networks identified several negative correlations between gene expression and resistance, which were missed by hierarchical clustering. Our results suggested the necessity of systematically evaluating the transporting systems that may play a major role in resistance in hepatoma. This may provide useful information to modify anticancer drug action in hepatoma.

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