Study on the mechanisms of HCV-mediated carcinogenesis

• Project/Area Number: 23590543
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Kobe University
• Principal Investigator: DENG Lin 神戸大学, 医学(系)研究科(研究院), 助教 (40437497)
• Co-Investigator(Kenkyū-buntansha): HOTTA Hak 神戸大学, 大学院医学研究科, 教授 (40116249)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: C型肝炎ウイルス / 発癌 / NS5A / SMYD3 / AGR3 / 感染症 / 癌化 / Ｃ型肝炎ウイルス / シグナル

Research Abstract

Hepatitis C Virus (HCV) NS5A is a multifunctional protein involved in HCV life cycle and HCV-induced liver pathologies. To elucidate the role of NS5A in HCV pathogenesis, we searched for host proteins interacting with NS5A by tandem affinity purification and identified a novel NS5A-interacting protein, SET and MYND domain-containing 3 (SMYD3), a histone methyltransferase involved in the proliferation of cancer cells. The interaction of NS5A with SMYD3 was confirmed by co-immunoprecipitation, proximity ligation assay, and confocal microscopy. NS5A predominately colocalized with SMYD3 in the cytoplasm. Moreover, the interaction between NS5A and SMYD3 transcriptionally activated AGR3, which is involved in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulfide isomerases. Taken together, these data suggest that the interaction between NS5A and SMYD3 causes hepatocytic dysfunction through upregulation of AGR3 expression.

Research Products

• [Journal Article] Prostaglandin D2 attenuates bleomycin-induced lung inflammation and pulmonary fibrosis. (2019)
  • Author(s): Tkeuchi A, Okubo K
  • Journal Title: Pros One Volume: 8 Pages: 0173147-0173147
  • NAID: 120006023321
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antiviral activity of extracts from Morinda citrifolia leaves and chlorophyll catabolites pheophorbide a and pyropheophorbide a, against hepatitis C virus (2014)
  • Author(s): Ratnoglik SL, Aoki C, Sudarmono P, Komoto M, Deng L, Shoji I, Fuchino H, Kawahara N, Hotta H.
  • Journal Title: Microbiol Immunol Volume: 58 Pages: 188-194
  • DOI: 10.1111/1348-0421.12133
  • Peer Reviewed
• [Journal Article] Anti-hepatitis C virus compounds obtained from Glycyrrhiza uralensis and other Glycyrrhiza species (2014)
  • Author(s): Adianti M, Aoki C, Komoto M, Deng L, Shoji I, Wahyuni TS, Lusida MI, Soetjipto, Fuchino H, Kawahara N, Hotta H
  • Journal Title: Microbiol Immunol Volume: 58(3) Pages: 180-187
  • DOI: 10.1111/1348-0421.12127
  • Peer Reviewed
• [Journal Article] Antiviral activities of Indonesian medicinal plants in the East Java region against hepatitis C virus (2013)
  • Author(s): Wahyuni TS, Tumewu L, Permanasari AA, Apriani E, Adianti M, Rahman A, Widyawaruyanti A, Lusida MI, Fuad A, Soetjipto D, Nasronudin D, Fuchino H, Kawahara N, Shoji I, Deng L, Aoki C, Hotta H.
  • Journal Title: Virol J Volume: 10 Pages: 259-259
  • DOI: 10.1186/1743-422x-10-259
  • NAID: 120005705279
  • Peer Reviewed
• [Journal Article] Polymorphisms of the core, NS3 and NS5A proteins of hepatitis C virus genotype 1b associate with development of hepatocellular carcinoma (2013)
  • Author(s): El-Shamy A, Shindo M, Shoji I, Deng L, Okuno T, Hotta H
  • Journal Title: Hepatology Volume: 58(2) Pages: 555-563
  • DOI: 10.1002/hep.26205
  • Peer Reviewed
• [Journal Article] HCV NS5A protein containing potential ligands for both Src homology 2 and 3 domains enhances autophosphorylation of Src family kinase Fyn in B cells (2012)
  • Author(s): Nakashima, K.
  • Journal Title: PLoS ONE Volume: 7(10)
  • DOI: 10.1371/journal.pone.0046634
  • Peer Reviewed
• [Journal Article] NS5A sequence heterogeneity of hepatitis C virus genotype 4a predicts clinical outcome of pegylated-interferon/ribavirin therapy in Egyptian patients. (2012)
  • Author(s): Ahmed EL-Shamy
  • Journal Title: J Clin Microbiol Volume: 50 Pages: 3886-3892
  • DOI: 10.1128/jcm.02109-12
  • Peer Reviewed
• [Journal Article] Hepatitis C virus infection suppresses GLUT2 gene expression via down-regulation of hepatocyte nuclear factor 1α. (2012)
  • Author(s): Matsui C
  • Journal Title: J Virol Volume: 86 Pages: 12903-11
  • DOI: 10.1128/jvi.01418-12
  • Peer Reviewed
• [Journal Article] Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotype 1b and high viral load. (2012)
  • Author(s): Kim SR, El-Shamy A, Imoto S, Kim KI, Ide YH, Deng L, Shoji I, Tanaka Y, Hasegawa Y, Ota M, Hotta H
  • Journal Title: J Gastroenterol Volume: 47(10) Pages: 1143-1151
  • DOI: 10.1007/s00535-012-0578-z
  • Peer Reviewed
• [Journal Article] Sequence heterogeneity in NS5A of hepatitis C virus genotypes 2a and 2b and clinical outcome of pegylated-interferon/ribavirin therapy (2012)
  • Author(s): El-Shamy A., Shoji I, Kim SR, Imoto S, Deng L, Yoon S, Fujisawa T, Tani S, Yano Y, Seo Y, Azuma T, Hotta H
  • Journal Title: PLoS One Volume: 55 Pages: 1-10
  • DOI: 10.1371/journal.pone.0030513
  • Peer Reviewed
• [Journal Article] Molecular mechanism of hepatitis C virus-induced glucose metabolic disorders (2012)
  • Author(s): Shoji I, Deng L, Hotta H
  • Journal Title: Front Microbiol Volume: 2 Pages: 278-278
  • DOI: 10.3389/fmicb.2011.00278
  • Peer Reviewed
• [Journal Article] A point mutation at Asn-534 that disrupts a conserved N-glycosylation motif of the E2 glycoprotein of hepatitis C virus markedly enhances the sensitivity to antibody neutralization. (2012)
  • Author(s): Sasayama M., Shoji I., Ide Y-H., Deng L., Hotta H
  • Journal Title: J Med Virol Volume: 84 Pages: 229-234
  • DOI: 10.1002/jmv.22257
  • Peer Reviewed
• [Journal Article] Generation of a recombinant reporter hepatitis C virus useful for the analyses of virus entry, intra-cellular replication and virion production (2012)
  • Author(s): Kamada K, Shoji I, Deng L, Aoki C, Ratnoglik SL, Wakita T, Hotta H
  • Journal Title: Microbes Infect Volume: 14(1) Pages: 69-78
  • DOI: 10.1016/j.micinf.2011.08.009
  • Peer Reviewed
• [Journal Article] Polymorphisms of hepatitis C virus non-structural protein 5A and core protein and clinical outcome of pegylated-interferon/ribavirin combination therapy (2012)
  • Author(s): El-Shamy A, Ide Y-H, Kim SR, Sasase N, Imoto S, Deng L, Shoji I, Hotta H
  • Journal Title: Intervirology Volume: 55 Pages: 1-11
  • DOI: 10.1159/000322219
  • Peer Reviewed
• [Journal Article] Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway (2011)
  • Author(s): Deng, L.
  • Journal Title: J Virol Volume: 85 Pages: 8556-68
  • DOI: 10.1128/jvi.00146-11
  • Peer Reviewed
• [Journal Article] Sequence heterogeneity of NS5A and core proteins of hepatitis C virus and virological responses to Pegylated-Interferon/Ribavirin combination therapy (2011)
  • Author(s): Saito T, Okumoto K, Haga H, Nishise Y, Ishii R, Sato C, Watanabe H, Okada A, Ikeda M, Togashi H, Ishikawa T, Terai S, Sakaida I, Kawata S
  • Journal Title: Microbiol Immunol Volume: 20 Pages: 1503-1510
  • DOI: 10.1111/j.1348-0421.2011.00331.x
  • NAID: 10031121486
  • Peer Reviewed
• [Presentation] C型肝炎ウイルス感染によるBax活性化の分子機序の解析 (2013)
  • Author(s): DENG Lin,陳明、勝二郁夫、堀田博
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2013-11-12
• [Presentation] HCV upregulates Bim through ROS/JNK signaling pathway leading to Bax-mediated apoptosis (2013)
  • Author(s): Lin Deng, Ming Chen, Ikuo Shoji, Hak Hotta
  • Organizer: 20th International Symposium on Hepatitis C Virus and Related Virus
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2013-10-09
• [Presentation] HCV NS5A interacts with SMYD3 and upregulates SMYD3-mediated expression of AGR3 mRNA (2013)
  • Author(s): Ming Chen, Xiang Gan, Lin Deng, Ikuo Shoji, Hak Hotta
  • Organizer: 20th International Symposium on Hepatitis C Virus and Related Virus
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2013-10-07
• [Presentation] Ｃ型肝炎ウイルス感染によるBax活性化の分子機序の解析 (2013)
  • Author(s): Lin Deng、陳 明、勝二郁夫、堀田博
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
• [Presentation] C型肝炎ウイルス感染によるBax活性化の分子機序の解析 (2012)
  • Author(s): DENG Lin、勝二郁夫、堀田博
  • Organizer: 第65回日本細菌学会関西支部総会
  • Place of Presentation: 神戸
  • Year and Date: 2012-11-17
• [Presentation] C型肝炎ウイルス感染による転写因子FoxO1脱リン酸化の分子機序の解析 (2012)
  • Author(s): DENG Lin、金子昌裕、河本真理、姜大鵬、勝二郁夫、堀田博
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2012-11-13
• [Presentation] C型肝炎ウイルスNS5A蛋白質の新規結合因子ヒストンメチル基転移酵素SMYD3の同定と機能解析 (2012)
  • Author(s): 陳明、甘翔、DENG Lin、勝二郁夫、堀田博
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2012-11-13
• [Presentation] Identification and characterization of a novel NS5A-interacting protein, SMYD3 (2012)
  • Author(s): Ming Chen, Xiang Gan, Lin Deng, Ikuo Shoji, Hak Hotta
  • Organizer: 19th International Symposium on Hepatitis C Virus and Related Virus
  • Place of Presentation: Venice, Italy
  • Year and Date: 2012-10-07
• [Presentation] Up-regulation of MAPK phosphatase 3 is involved in HCV-induced suppression of FoxO1 phosphorylation (2012)
  • Author(s): Lin Deng, Ming Chen, Dapeng Jiang, Ikuo Shoji, Hak Hotta
  • Organizer: 19th International Symposium on Hepatitis C Virus and Related Virus
  • Place of Presentation: Venice, Italy
  • Year and Date: 2012-10-06
• [Presentation] Ｃ型肝炎ウイルス感染による転写因子FoxO1脱リン酸化の分子機序の解析 (2012)
  • Author(s): Lin Deng, 金子 昌裕、河本 真理、姜 大鵬、勝二 郁夫、堀田 博
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
• [Presentation] C型肝炎ウイルスNS5Aの新規結合タンパク質であるヒストンメチル基転移酵素SMYD3の同定 (2011)
  • Author(s): 甘翔、DENG Lin、陳明、井出良浩、勝二郁夫、堀田博
  • Organizer: 第64回日本細菌学会関西支部総会
  • Place of Presentation: 大阪府堺市
  • Year and Date: 2011-11-19
• [Presentation] Molecular mechanisms involved in HCV infection-induced hepatic gluconeogenesis (2011)
  • Author(s): Lin Deng, Ikuo Shoji, Wataru Ogawa, Shusaku Kaneda, Tomoyoshi Soga, Da-peng Jiang, Yoshi-Hiro Ide, Hak Hotta
  • Organizer: International Union of Microbiological Societies 2011 Congress
  • Place of Presentation: 札幌
  • Year and Date: 2011-09-15
• [Presentation] Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway (2011)
  • Author(s): Lin Deng, Ikuo Shoji, Wataru Ogawa, Shusaku Kaneda, Tomoyoshi Soga, Da-peng Jiang, Yoshi-Hiro Ide, Hak Hotta
  • Organizer: 18th International Symposium on Hepatitis C Virus and Related Virus
  • Place of Presentation: Seattle, USA
  • Year and Date: 2011-09-10
• [Presentation] C型肝炎ウイルスは酸化ストレスを介して糖新生を亢進し糖尿病発症に関与する (2011)
  • Author(s): DENG Lin、勝二郁夫、堀田博
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-03
• [Presentation] C型肝炎ウイルスNS5Aの新規結合タンパク質であるヒストンメチル基転移酵素SMYD3の同定 (2011)
  • Author(s): Lin Deng
  • Organizer: 第64回日本細菌学会関西支部総会
  • Place of Presentation: 大阪府 堺市
• [Presentation] Ｃ型肝炎ウイルス感染によるBax活性化の分子機序の解析
  • Author(s): Lin Deng, 勝二郁夫、堀田博
  • Organizer: 第65回日本細菌学会関西支部総会
  • Place of Presentation: 神戸
• [Remarks] 第47回日本肝臓学会総会優秀演題賞受賞
  • URL: http://www.med.kobe-u.ac.jp/info/2011/deng_110607.html
• [Remarks] 社団法人日本肝臓学会第10回MSD Award 2011受賞
  • URL: http://www.med.kobe-u.ac.jp/info/2011/deng_111101.html
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/micro/
• [Remarks] 神戸大学大学院医学研究科微生物学分野
  • URL: http://www.med.kobe-u.ac.jp/micro/
• [Remarks] 第47回日本肝臓学会総会優秀演題賞受賞
  • URL: http://www.med.kobe-u.ac.jp/info/2011/deng_111101.html
• [Remarks] 社団法人日本肝臓学会第10回MSD Award 2011受賞
  • URL: http://www.med.kobe-u.ac.jp/info/2011/deng_110607.html