Analysis of the roles of linear polyubiquitin chains and Sharpin in hepatocellular carcinoma

• Project/Area Number: 25460981
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Tateishi Ryosuke 東京大学, 医学部附属病院, 特任講師 (50444089)
• Co-Investigator(Kenkyū-buntansha): TANAKA Yasuo 東京大学, 医学部附属病院, 助教 (40422290)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝臓 / 肝細胞癌 / Sharpin / 癌関連遺伝子 / 浸潤能 / ユビキチン / 直鎖型ポリユビキチン鎖 / SHARPIN

Outline of Final Research Achievements

Sharpin is one of the components of the LUBAC, which specifically generates linear polyubiquitin chains to activate NF-kB pathway. Sharpin is also reported to be up-regulated in various types of cancers including HCC and implicated in　cancer progression. In this study, we showed that Sharpin transcription was　up-regulated in HCC tissues, and significantly correlated with tumor size and histology. Increased expression of Sharpin enhanced the invasion of hepatoma　cells, and cDNA microarray analysis identified that Versican, an extracellular matrix proteoglycan, was also up-regulated in Sharpin expressing cells. Knocking down of Versican greatly attenuated the invasion of hepatoma. Furthermore, Sharpin overexpression resulted in activation of Versican promoter activity.　Taken together, these results suggest that Sharpin plays crucial roles in tumor-invasiveness during cancer progression through transactivating Versican.

Research Products

• [Journal Article] Impact of serum ferritin level on hepatocarcinogenesis in chronic hepatitis C patients. (2015)
  • Author(s): Uchino K, Tateishi R, Fujiwara N, Minami T, Sato M, Enooku K, Nakagawa H, Asaoka Y, Kondo Y, Yoshida H, Moriya K, Shiina S, Omata M, Koike K.
  • Journal Title: Hepatol Res. Volume: epub Issue: 4 Pages: 259-68
  • DOI: 10.1111/hepr.12517
  • Peer Reviewed
• [Journal Article] Comparison of improved prognosis between hepatitis B- and hepatitis C-related hepatocellular carcinoma. (2015)
  • Author(s): Minami T, Tateishi R, Shiina S, Nakagomi R, Kondo M, Fujiwara N, Mikami S, Sato M, Uchino K, Enooku K, Nakagawa H, Asaoka Y, Kondo Y, Yoshida H, Koike K.
  • Journal Title: Hepatol Res. Volume: epub Issue: 10
  • DOI: 10.1111/hepr.12468
  • Peer Reviewed
• [Journal Article] Impact of serum levels of interleukin-6 and adiponectin on all-cause, liver-related, and liver-unrelated mortality in chronic hepatitis C patients. (2015)
  • Author(s): Nakagawa H, Fujiwara N, Tateishi R, Arano T, Nakagomi R, Kondo M, Minami T, Sato M, Uchino K, Enooku K, Asaoka Y, Kondo Y, Shiina S, Yoshida H, Koike K.
  • Journal Title: J Gastroenterol Hepatol. Volume: 30 Issue: 2 Pages: 379-88
  • DOI: 10.1111/jgh.12719
  • Peer Reviewed
• [Journal Article] Tumor markers are more useful in patients undergoing surveillance for hepatocellular carcinoma with unreliable results by ultrasonography. (2015)
  • Author(s): Mikami S, Tateishi R, Hagiwara S, Sato M, Minami T, Uchino K, Enooku K, Sato T, Nakagawa H, Masuzaki R, Asaoka Y, Kondo Y, Shiina S, Ikeda H, Omata M, Yoshida H, Koike K.
  • Journal Title: Hepatol Res. Volume: 45 Issue: 4 Pages: 415-22
  • DOI: 10.1111/hepr.12365
  • Peer Reviewed
• [Journal Article] Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. (2015)
  • Author(s): Tateishi R, Okanoue T, Fujiwara N, Okita K, Kiyosawa K, Omata M, Kumada H, Hayashi N, Koike K.
  • Journal Title: J Gastroenterol. Volume: 50 Issue: 3 Pages: 350-60
  • DOI: 10.1007/s00535-014-0973-8
  • Peer Reviewed
• [Journal Article] Increased serum autotaxin levels in hepatocellular carcinoma patients were caused by background liver fibrosis but not by carcinoma (2014)
  • Author(s): Kondo M, Ishizawa T, Enooku K, Tokuhara Y, Ohkawa R, Uranbileg B, Nakagawa H, Tateishi R, Yoshida H, Kokudo N, Koike K, Yatomi Y, Ikeda H
  • Journal Title: Clin Chim Acta Volume: 433C Pages: 128-134
  • DOI: 10.1016/j.cca.2014.03.006
  • Peer Reviewed
• [Journal Article] Increased Serum Mitochondrial Creatine Kinase Activity as a Risk for Hepatocarcinogenesis in Chronic Hepatitis C Patients. (2014)
  • Author(s): Enooku K, Nakagawa H, Soroida Y, Ohkawa R, Kageyama Y, Uranbileg B, Watanabe N, Tateishi R, Yoshida H, Koike K, Yatomi Y, Ikeda H.
  • Journal Title: Int J Cancer Volume: epub Issue: 4 Pages: 871-879
  • DOI: 10.1002/ijc.28720
  • Peer Reviewed
• [Journal Article] High ubiquitous mitochondrial creatine kinase expression in hepatocellular carcinoma denotes a poor prognosis with highly malignant potential. (2013)
  • Author(s): Uranbileg B, Enooku K, Soroida Y, Ohkawa R, Kudo Y, Nakagawa H, Tateishi R, Yoshida H, Shinzawa S, Moriya K, Ohtomo N, Nishikawa T, Inoue Y, Tomiya T, Kojima S, Matsuura T, Koike K, Yatomi Y, Ikeda H.
  • Journal Title: Int J Cancer. Volume: 134 Issue: 9 Pages: 2189-98
  • DOI: 10.1002/ijc.28547
  • Peer Reviewed
• [Journal Article] Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. (2013)
  • Author(s): He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, Shalapour S, Seki E, Yost SE, Jepsen K, Frazer KA, Harismendy O, Hatziapostolou M, Iliopoulos D, Suetsugu A, Hoffman RM, Tateishi R, Koike K, Karin M.
  • Journal Title: Cell. Volume: 155 Issue: 2 Pages: 384-396
  • DOI: 10.1016/j.cell.2013.09.031
  • Peer Reviewed
• [Presentation] Sharpin cooperates with Wnt pathway to transactivate Versican expression to promote HCC invasion (2016)
  • Author(s): Yasuo Tanaka, Keisuke Tateishi, Takuma Nakatsuka , Yotaro Kudo, Yoshinari Asaoka, Ryosuke Tateishi, Kazuhiko Koike.
  • Organizer: APASL(Asian Pacific Association for the Study of the Liver) 2016
  • Place of Presentation: グランドプリンスホテル新高輪（東京都品川区）
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] 新規がん遺伝子候補 Sharpinの 肝癌進展における役割の解明 (2015)
  • Author(s): 田中 康雄、立石 敬介、中塚 拓馬、宮林 弘至、高橋 良太、山本 恵介、工藤 洋太郎、浅岡 良成、伊地知 秀明、建石 良介、小池 和彦
  • Organizer: 日本消化器関連学会機構 JDDW 2015
  • Place of Presentation: グランドプリンスホテル新高輪（東京都品川区）
  • Year and Date: 2015-10-08
• [Presentation] Sharpin promotes invasion of hepatocellular carcinoma through trans-activating Versican expressi (2014)
  • Author(s): Yasuo Tanaka, Keisuke Tateishi, Takuma Nakatsuka , Yotaro Kudo, Yoshinari Asaoka, Ryosuke Tateishi, Kazuhiko Koike
  • Organizer: AASLD 2014 Annual Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11