MicroRNAs as early predictors of efficacy and drug resistance to molecularly targeted therapy in hepatocellular carcinoma

• Project/Area Number: 21K15928
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kagawa University
• Principal Investigator: Oura Kyoko 香川大学, 医学部附属病院, 助教 (80834639)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肝細胞癌 / microRNA / atezolizumab / bevacizumab / 分子標的治療薬 / 薬剤耐性 / Atezolizumab / Bevacizumab

Outline of Research at the Start

まずHCC細胞株を用いた基礎研究を行い、分子標的治療薬によって細胞内外で変化する血管新生分子群とmiRNAを網羅的に解析する。次にHCC患者の臨床検体を用いた検討を行い、治療前後の血清サンプルにおいてmiRNAの変化を解析する。分子標的治療薬の制御機構と関連するmiRNAを解析することによって、治療効果・薬剤耐性を早期予測し、治療成績向上につながるバイオマーカーを同定する。薬剤耐性に関連するmiRNAを標的とした治療戦略の可能性についても検討する。

Outline of Final Research Achievements

Sixty-six patients with uHCC treated with Atezo/Bev were included. Comparing 44 patients in the response group with 22 patients in the non-response group, 10 miRNAs were significantly elevated before treatment in the response group, especially miR-485-3p, which was higher than in the non-response group and further elevated on the next day and 3 weeks later. Serum VEGF levels before treatment were not significantly different, but both groups decreased to below detection sensitivity the next day, and the 3-week/pre-treatment ratio was significantly lower in the response group than in the non-response group. In vitro, miR-485-3p transfection suppressed migration and proliferation in HuH-7, enhanced PIAS3 expression, and suppressed STAT3/VEGF expression, which were more pronounced in cells co-cultured with HuVEC.

Academic Significance and Societal Importance of the Research Achievements

Atezo/Beva併用療法において、血清miR-485-3pはVEGFより鋭敏に変化するため、早期治療効果を予測するのに有用である。PIAS3/STAT3/VEGF signalが関連しており、今後バイオマーカーや創薬開発に臨床応用できる可能性がある。

Research Products

• [Presentation] miR-485-3p as a predictive biomarker in Ateozo/Beva therapy and analysis of PIAS3/STAT3/VEGF signal (2024)
  • Author(s): Kyoko Oura
  • Organizer: APASL 2024 Kyoto
  • Int'l Joint Research
• [Presentation] 肝細胞癌に対するAteozolizumab/Bevacizumab併用療法におけるcirculating microRNAの早期効果予測マーカーとしての有用性と血管新生に関する制御機構の解析 (2023)
  • Author(s): 大浦杏子
  • Organizer: 第24回西部肝臓学会
• [Presentation] 進行肝細胞癌におけるAteozolizumab/Bevacizumab併用療法中の早期病勢進行(PD)予測因子としての末梢血血管新生分子の解析 (2022)
  • Author(s): 大浦杏子
  • Organizer: 第58回日本肝臓学会総会
• [Presentation] Usefulness of serum angiogenic molecules as predictive biomarkers of the early disease progression in atezolizumab plus bevacizumab combination therapy for hepatocellular carcinoma (2022)
  • Author(s): Kyoko Oura
  • Organizer: The 31st Conference of the Asian Pacific Association for the Study of the Liver
  • Int'l Joint Research
• [Presentation] 肝細胞癌に対するAteozolizumab/Bevacizumab併用療法における早期病勢進行(PD)の予測マーカーとしての血清血管新生分子測定の有用性 (2022)
  • Author(s): 大浦杏子
  • Organizer: 第58回日本肝癌研究会