Analysis of regulatory system of hepatocellular carcinoma progression by heat shock protein complex network

• Project/Area Number: 17K09417
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: Matsushima-Nishiwaki Rie 岐阜大学, 大学院医学系研究科, 助教 (90734202)
• Co-Investigator(Kenkyū-buntansha): 高井 光治 岐阜大学, 大学院医学系研究科, 特任准教授 (70402196) ; 清水 雅仁 岐阜大学, 大学院医学系研究科, 教授 (90402198)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝細胞癌 / 低分子量ストレスタンパク質 / 細胞遊走 / ストレス蛋白質 / 低分子量 / 細胞運動 / 肝癌 / ストレスタンパク質

Outline of Final Research Achievements

Small heat shock proteins (HSPBs) regulate a variety of cell functions. 　HSPBs are known to make protein complex with various molecular target proteins and regulate them. In the present study, we investigated whether the HSPB complex is implicated in hepatocellular carcinoma cell migration. Our results strongly suggest that HSP22 make the protein complex with PI3 kinase and represses hepatocellular carcinoma progression, especially hepatocellular carcinoma cell migration, by down-regulation of the PI3K/AKT signaling pathway. In addition, we also found that HSP22 and HSP20 independently make the protein complex with HSP27 in HCC.

Academic Significance and Societal Importance of the Research Achievements

低分子量ストレス蛋白質（HSPB)による肝細胞癌の進展制御について詳細を検討する研究は私共のHSP27及びHSP20によるが肝がん細胞の増殖、進展を制御している機構についての研究が世界に先んじている。本研究において私共が見出したHSP22がPI3 kinaseを分子標的として複合体を形成し、肝がん 細胞の遊走を抑制的に制御しているという結果、および肝がん細胞の増殖、遊走を制御するHSP20とHSP22がそれぞれ独立にHSP27と複合体を形成するという結果は低分子量ストレスタンパク質を標的とした新 たな肝細胞がん治療法、特に肝がんの転移に対する治療法の確立に大いに資すると考えられた。

Research Products

• [Journal Article] Quercetin suppresses the migration of hepatocellular carcinoma cells stimulated by hepatocyte growth factor or transforming growth factor-α: Attenuation of AKT signaling pathway. (2020)
  • Author(s): Yamada N, Matsushima-Nishiwaki R, and Kozawa O.
  • Journal Title: Archives of Biochemistry and Biophysics Volume: 682 Pages: 108296-108296
  • DOI: 10.1016/j.abb.2020.108296
  • Peer Reviewed / Open Access
• [Journal Article] Olive oil polyphenols suppress the TGF-α-induced migration of hepatocellular carcinoma cells. (2019)
  • Author(s): Yamada N, Matsushima-Nishiwaki R, Masue A, Taguchi K and Kozawa O.
  • Journal Title: Biomedical Reports. Volume: 1 Pages: 1-5
  • DOI: 10.3892/br.2019.1215
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine 1-phosphate (S1P) reduces hepatocyte growth factor-induced migration of hepatocellular carcinoma cells via S1P receptor 2. (2018)
  • Author(s): Matsushima-Nishiwaki R, Yamada N, Fukuchi K, Kozawa O.
  • Journal Title: PLoS One. Volume: 13 Issue: 12 Pages: e0209050-e0209050
  • DOI: 10.1371/journal.pone.0209050
  • Peer Reviewed / Open Access
• [Journal Article] Heat shock protein 22 (HSPB8) reduces the migration of hepatocellular carcinoma cells through the suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway. (2017)
  • Author(s): Matsushima-Nishiwaki R, Toyoda H, Takamatsu R, Yasuda E, Okuda S, Maeda A, Kaneoka Y, Yoshimi N, Kumada T, Kozawa O.
  • Journal Title: Biochim. Biophys Acta-Mol. Basis Dis. Volume: 1863 Pages: 1629-1639
  • Peer Reviewed
• [Presentation] スフィンゴシン1－リン酸 (S1P)はS1P受容体 2を介してHGF刺激により誘導される肝癌細胞の遊走を抑制する (2019)
  • Author(s): 西脇 理英、山田 紀子、小澤 修
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] HSP22 reduces the migration of hepatocellular carcinoma cells through the suppression of the PI3K/AKT pathway. HSP22はPI3K/AKT経路を阻害し肝癌細胞の遊走を抑制する (2018)
  • Author(s): Rie Matsushima-Nishiwaki, Naoki Yoshimi, Osamu Kozawa.
  • Organizer: 第77回日本癌学会学術総会