Investigation of the mechanism for suppression of carcinogenesis in familial adenomatous polyposis mediated by ABCC3 and ROS with NSAIDs.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15477
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tohoku University
• Principal Investigator: Minoru Kobayashi 東北大学, 大学病院, 助教 (40885547)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ABCC3 / MRP3 / 大腸癌 / 家族性大腸腺腫症 / デオキシコール酸 / Wntシグナル / MAPKシグナル

Outline of Final Research Achievements

We here explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. Gene expression analysis of colorectal adenoma isolated from FAP patients revealed that ABCC3 were downregulated as early as at the stage of adenoma formation. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid, a secondary bile acid, respectively, in colorectal cancer cells. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that nonsteroidal anti-inflammatory drugs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of familial adenomatous polyposis. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling.

Free Research Field

大腸癌、家族性大腸腺腫症

Academic Significance and Societal Importance of the Research Achievements

本研究の結果から、FAPの腺腫においてABCC3の発現が低下することで、細胞内にDCAが蓄積し、それにより発癌シグナルであるMAPKシグナルが活性化することが示唆された。大腸癌の発癌過程におけるこれらの変化は、これまで報告されておらず、新規発癌機構の解明に繋がることが期待される。また、NSAIDsはABCC3の発現を亢進させることで、DCAの細胞内濃度の低下を介して発癌を抑制する働きをする可能性がある。この結果は、NSAIDsのFAPに対する新たな発癌抑制機構の存在を示唆するものであり、今後この機構を詳細に解明することによって新規発癌抑制戦略に繋がる可能性がある。