Investigation of the HSF1 signaling pathway as the molecular targeted therapies for hepatocellular carcinoma.

• Project/Area Number: 26460982
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Yokohama City University
• Principal Investigator: Makoto Chuma 横浜市立大学, 附属市民総合医療センター, 准教授 (30360910)
• Co-Investigator(Kenkyū-buntansha): 坂本 直哉 北海道大学, 医学研究科, 教授 (10334418)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝癌 / 分子標的治療 / HSF1 / Heat shock factor / ストレス関連遺伝子 / 酸化ストレス / 脂肪性肝炎

Outline of Final Research Achievements

HSF1, a major transactivator of stress responses, has been implicated in carcinogenesis in various organs. We investigated to clarify the functional role of HSF1 in HCC. Tumorigenicity was significantly reduced in orthotopic mice with HSF1-KD cells compared to those with HSF1-control cells. Reduced tumorigenesis in HSF1-KD cells appeared attributable to increased apoptosis and decreased proliferation. Tumor necrosis factor α-induced apoptosis was increased in HSF1-KD cells and HSF1-/- mouse. Decreased expression of IKKγ, a positive regulator of nuclear factor κB, was also observed in HSF1-KD cells and HSF1-/- mouse hepatocytes. Clinicopathological analysis demonstrated frequent overexpression of HSF1 in human HCCs. Significant correlations between HSF1 protein levels and prognosis were also observed. In summary, these results identify a mechanistic link between HSF1 and liver tumorigenesis and may provide as a potential molecular target for the development of anti-HCC therapies.

Research Products

• [Journal Article] Anti-adipogenic and antiviral effects of l-carnitine on hepatitis C virus infection. (2016)
  • Author(s): Tsukuda Y, Suda G, Tsunematsu S, Ito J, Sato F, Terashita K, Nakai M, Sho T, Maehara O, Shimazaki T, Kimura M, Morikawa K, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Sakamoto N
  • Journal Title: J Med Virol Volume: 89 Issue: 5 Pages: 857-866
  • DOI: 10.1002/jmv.24692
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma (2016)
  • Author(s): Terashita K, Chuma M, Hatanaka Y, Hatanaka K, Mitsuhashi T, Yokoo H, Ohmura T, Ishizu H, Muraoka S, Nagasaka A, Tsuji T, Yamamoto Y, Kurauchi N, Shimoyama N, Toyoda H, Kumada T, Kaneoka Y, Maeda A, Ogawa K, Natsuizaka M, Kamachi H, Kakisaka T, Kamiyama T, Taketomi A, Matsuno Y, Sakamoto N
  • Journal Title: J Clin Pathol Volume: in press Issue: 7 Pages: 593-599
  • DOI: 10.1136/jclinpath-2015-203115
  • Peer Reviewed
• [Journal Article] New molecularly targeted therapies against advanced hepatocellular carcinoma: From molecular pathogenesis to clinical trials and future directions. (2015)
  • Author(s): Chuma M, Terashita K, Sakamoto N
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 10
  • DOI: 10.1111/hepr.12459
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intratumoral artery on contrast-enhanced computed tomography imaging: differentiating intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma (2015)
  • Author(s): Tsunematsu S, Chuma M, Kamiyama T, Miyamoto N, Yabusaki S, Hatanaka K, Mitsuhashi T, Kamachi H, Yokoo H, Kakisaka T, Tsuruga Y, Orimo T, Wakayama K, Ito J, Sato F, Terashita K, Nakai M, Tsukuda Y, Sho T, Suda G, Morikawa K, Natsuizaka M, Nakanishi M, Ogawa K, Taketomi A, Matsuno Y, Sakamoto N
  • Journal Title: Abdom Imaging Volume: 40 Issue: 6 Pages: 1492-9
  • DOI: 10.1007/s00261-015-0352-9
  • Peer Reviewed
• [Journal Article] Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor κB/mitogen-activated protein kinase. (2014)
  • Author(s): Chuma M, Sakamoto N, Nakai A, Hige S, Nakanishi M, Natsuizaka M, Suda G, Sho T, Hatakaka K, Matsuno Y, Yokoo H, Kamiyama T, Taketomi A, Fujii G, Tashiro K, Hikiba Y, Fujimoto M, Asaka M, Maeda S
  • Journal Title: Carcinogenesis Volume: Epub ahead of print Issue: 2 Pages: 272-281
  • DOI: 10.1093/carcin/bgt343
  • Peer Reviewed
• [Presentation] Molecular Pathogenesis for HCC Development: HSF1 Potential Molecular Target for HCC Therapies (2016)
  • Author(s): Chuma M, Sakamoto N, Yokoo H, Kamiyama T, Taketomi A, Maeda S.
  • Organizer: The 25th Asian Pacific Association for the Study of the Liver
  • Place of Presentation: Tokyo
  • Year and Date: 2016-02-22
  • Int'l Joint Research
• [Presentation] 肝細胞癌の早期再発予測に関する血清バイオマーカー (2014)
  • Author(s): 中馬 誠、坂本 直哉、神山 俊哉
  • Organizer: 第50回肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-30
• [Book] Heat shock factor (2015)
  • Author(s): Chuma M
  • Total Pages: 8
  • Publisher: Springer
• [Book] HSF supports cancer (2015)
  • Author(s): Chuma M
  • Total Pages: 20
  • Publisher: Springer