Development of new therapeutic methods targeting cytokine regulators in cancer-related fibroblasts

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16352
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Gunma University
• Principal Investigator: Tsukagoshi Mariko 群馬大学, 大学院医学系研究科, 助教 (60781317)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 癌関連線維芽細胞 / 肝癌 / 癌微小環境 / GPR68 / サイトカイン

Outline of Final Research Achievements

Hepatocellular carcinoma (HCC) is a malignancy that is challenging to treat. Cancer-associated fibroblasts (CAFs) are reported to promote the malignant behavior of HCC cells via cytokines. We focused on the function of CAFs in the progression of HCC and aimed to develop a new therapeutic method targeting G Protein-Coupled Receptor 68 (GPR68).
The expression of GPR68 in HCC CAFs was increased by acidic condition, and the proliferation of CAFs was promoted. In addition, the production of cytokines IL-6 and IL-8 was increased. The production of cytokines was weakened by the knockdown of GPR68. Additionally, the cancer-promoting effect of CAFs was weakened by the knockdown of GPR68 by siRNA.These results indicate that the regulation of cytokine secretion by GPR68 may suppress the HCC-promoting effect of CAFs and suppress the progression of HCC.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

肝癌は予後不良で、ウイルス肝炎感染を伴わない肝癌が増加傾向であり、新たな治療戦略が求められている。近年、癌微小環境における癌関連線維芽細胞(CAF)の機能が注目されている。本研究ではCAFがサイトカインを介して肝癌進行に関わることに注目し、サイトカイン制御因子G protein-coupled receptor 68(GPR68)が肝癌進展に与える影響を検討した。GPR68によるサイトカイン分泌制御により肝癌CAFの活性が抑制され、肝癌の進展が抑制できる可能性が示された。今後GPR68は肝癌の新たな治療ターゲットとなり、既存制癌剤併用での治療効果増強等、革新的治療に結びつく可能性がある。