ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression is downregulated in colorectal cancer through the Wnt/β‐catenin signaling pathway. 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—in 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‐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.

中文翻译：

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ABCC3 的下调通过结直肠癌细胞中脱氧胆酸的积累激活 MAPK 信号传导

ABCC3（也称为 MRP3）是胆汁酸的 ATP 结合盒转运蛋白，其表达在结直肠癌中通过 Wnt/β-catenin 信号通路下调。然而，目前尚不清楚 ABCC3 表达下调如何促进结直肠癌发生。我们探讨了 ABCC3 在结直肠癌进展中的作用，特别是关注胆汁酸输出的调节。对从家族性腺瘤性息肉病患者分离的结直肠腺瘤的基因表达分析显示，与胆汁酸分泌相关的基因（包括ABCC3）早在腺瘤形成阶段就被下调。 ABCC3的敲低或过度表达分别增加或降低结直肠癌细胞中脱氧胆酸（一种次级胆汁酸）的细胞内浓度。 ABCC3 的强制表达抑制了脱氧胆酸诱导的 MAPK 信号激活。最后，我们发现非甾体抗炎药增加结直肠癌细胞中ABCC3的表达，表明ABCC3可能成为家族性腺瘤性息肉病治疗干预的靶点之一。因此，我们的数据表明，ABCC3 表达的下调通过调节细胞内胆汁酸的积累和 MAPK 信号传导的活性，有助于结直肠癌的发生。