Targeting extracellular matrix proteoglycan Versican for diagnosis and therapy of hepatocellular carcinoma

• Project/Area Number: 16K09342
• 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): 田中 康雄 東京大学, 医学部附属病院, 助教 (40422290)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 細胞外マトリックス / 浸潤 / 転移 / Versican / 細胞外マトリックスプロテオグリカン / Sharpin / 肝細胞癌 / 糖タンパク質 / バイオマーカー / 癌関連遺伝子

Outline of Final Research Achievements

Versican is a functional extracellular matrix proteoglycan that plays important roles in tumor progression and invasion. In this study, we demonstrated that Sharpin interacted with β-catenin and induced Versican transcription synergistically with Wnt/β-catenin pathway activation, potentially contributing to hepatocellular carcinoma development. Under Wnt pathway activation, Sharpin and Versican could be an attractive therapeutic target for hepatocellular carcinoma.

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌患者の生命予後は手術やラジオ波焼灼療法を中心とした局所療法による根治的治療により伸びているが、肝細胞癌の浸潤や遠隔転移は、肝細胞癌患者の予後を悪化させる主な原因の一つである。本研究では、肝細胞癌の浸潤を引き起こすと考えられている分子である細胞外マトリックスプロテオグリカンの一つVersicanに着目し、その発現調節機序と新規治療標的としての可能性を示し、本分子を標的とした治療が肝癌患者の予後改善へ寄与できる可能性が考えられた。

Research Products

• [Journal Article] Proteoglycans Are Attractive Biomarkers and Therapeutic Targets in Hepatocellular Carcinoma. (2018)
  • Author(s): Tanaka Y, Tateishi R, Koike K.
  • Journal Title: Int J Mol Sci. Volume: 19 Issue: 10 Pages: 3070-3070
  • DOI: 10.3390/ijms19103070
  • Peer Reviewed / Open Access
• [Journal Article] Serum levels of ferritin do not affect the prognosis of patients with hepatocellular carcinoma undergoing radiofrequency ablation (2018)
  • Author(s): Uchino Koji、Tateishi Ryosuke、Nakagomi Ryo、Fujiwara Naoto、Minami Tatsuya、Sato Masaya、Enooku Kenichiro、Nakagawa Hayato、Asaoka Yoshinari、Kondo Yuji、Shibahara Junji、Shiina Shuichiro、Koike Kazuhiko
  • Journal Title: PLOS ONE Volume: 13 Issue: 7 Pages: e0200943-e0200943
  • DOI: 10.1371/journal.pone.0200943
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic IRS1 and beta-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients (2018)
  • Author(s): Enooku Kenichiro、Kondo Mayuko、Fujiwara Naoto、Sasako Takayoshi、Shibahara Junji、Kado Akira、Okushin Kazuya、Fujinaga Hidetaka、Tsutsumi Takeya、Nakagomi Ryo、Minami Tatsuya、Sato Masaya、Nakagawa Hayato、Kondo Yuji、Asaoka Yoshinari、Tateishi Ryosuke、Ueki Kohjiro、Ikeda Hitoshi、Yoshida Haruhiko、et al.
  • Journal Title: Journal of Gastroenterology Volume: 53 Issue: 12 Pages: 1261-1275
  • DOI: 10.1007/s00535-018-1472-0
  • Peer Reviewed
• [Journal Article] CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity (2018)
  • Author(s): Fujiwara Naoto、Nakagawa Hayato、Enooku Kenichiro、Otsuka Motoyuki、Tateishi Keisuke、Koike Kazuhiko
  • Journal Title: Gut Volume: 67 Issue: 8 Pages: 1493-1504
  • DOI: 10.1136/gutjnl-2017-315193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1 (2018)
  • Author(s): Fujiwara Hiroaki、Tateishi Keisuke、Kato Hiroyuki、Nakatsuka Takuma、Yamamoto Keisuke、Tanaka Yasuo、Ijichi Hideaki、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Matsubara Saburo、Nakai Yousuke、Koike Kazuhiko
  • Journal Title: Cancer Science Volume: 109 Issue: 11 Pages: 3602-3610
  • DOI: 10.1111/cas.13784
  • Peer Reviewed
• [Journal Article] Mortality and hemorrhagic complications associated with radiofrequency ablation for treatment of hepatocellular carcinoma in patients on hemodialysis for end-stage renal disease: A nationwide survey. (2017)
  • Author(s): Sato M, Tateishi R, Yasunaga H, Matsui H, Horiguchi H, Fushimi K, Koike K.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 11 Pages: 1873-1878
  • DOI: 10.1111/jgh.13780
  • Peer Reviewed / Open Access
• [Journal Article] Emerging role of SHARPIN in hepatocellular carcinoma progression (2017)
  • Author(s): Tanaka Y, Tateishi R, Koike K
  • Journal Title: Cancer Cell Microenviron. Volume: 4
  • DOI: 10.14800/ccm.1540
  • Peer Reviewed / Open Access
• [Journal Article] The ADOPT-LC score: a novel predictive index of in-hospital mortality of cirrhotic patients following surgical procedures, based on a national survey. (2017)
  • Author(s): Sato M, Tateishi R, Yasunaga H, Horiguchi H, Matsui H, Yoshida H, Fushimi K, Koike K.
  • Journal Title: Hepatol Res. Volume: 47 Issue: 3
  • DOI: 10.1111/hepr.12719
  • Peer Reviewed
• [Journal Article] Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression. (2016)
  • Author(s): Tanaka Y, Tateishi K, Nakatsuka T, Kudo Y, Takahashi R, Miyabayashi K, Yamamoto K, Asaoka Y, Ijichi H, Tateishi R, Shibahara J, Fukayama M, Ishizawa T, Hasegawa K, Kokudo N, Koike K.
  • Journal Title: Oncogenesis. Volume: 5 Issue: 12 Pages: e277-e277
  • DOI: 10.1038/oncsis.2016.76
  • Peer Reviewed / Open Access
• [Journal Article] The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma. (2016)
  • Author(s): Minami T, Tateishi R, Nakagomi R, Fujiwara N, Sato M, Enooku K, Nakagawa H, Asaoka Y, Kondo Y, Shiina S, Koike K
  • Journal Title: J Hepatol. Volume: 65 Issue: 6 Pages: 1272-1273
  • DOI: 10.1016/j.jhep.2016.07.043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] 新規癌関連遺伝子 Sharpin は細胞外マトリックスプロテオグリカン Versican の発現を介して肝癌進展に寄与する (2017)
  • Author(s): 田中 康雄、立石敬介、建石良介、小池和彦
  • Organizer: 第54回日本臨床分子医学会学術集会