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However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We explored the role of ABCC3 in the progression of colorectal cancer\u2014in particular, focusing on the regulation of bile acid export. Gene expression analysis of colorectal adenoma isolated from familial adenomatous polyposis patients revealed that genes related to bile acid secretion including 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\u2010induced activation of MAPK signaling. Finally, we found that nonsteroidal anti\u2010inflammatory 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.<\/jats:p>","DOI":"10.1111\/cas.16132","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T03:59:09Z","timestamp":1712116749000},"page":"1778-1790","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Downregulation of <scp>ABCC3<\/scp> activates <scp>MAPK<\/scp> signaling through accumulation of deoxycholic acid in colorectal cancer cells"],"prefix":"10.1111","volume":"115","author":[{"given":"Yukihiro","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Cell Proliferation, ART, Graduate School of Medicine Tohoku University  Sendai Japan"},{"name":"Department of Surgery, Graduate School of Medicine Tohoku University  Sendai 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