Wnt-β-catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer

Abstract

We determined the gene expression profiles for 48 ATP binding cassette (ABC) transporters in matched colon cancer and normal colon tissues in order to provide insight into the mechanisms underlying expression of transporters related to colon carcinogenesis. The expression of ABCB1, ABCC1, ABCC2, ABCC3, and ABCG2 was altered in association with colon carcinogenesis. Among these transporters, the expression of ABCC3 was repressed by Wnt signaling pathway in colon cancer cell lines. Knockdown of the pathway components transcription factor 7-like 2 (TCF7L2) or β-catenin thus increased ABCC3 expression, whereas activation of Wnt signaling with inhibitors of glycogen synthase kinase–3β (GSK-3β) reduced it. ChIP and luciferase reporter assays also showed that TCF7L2 binds to the ABCC3 locus and regulates its expression. Finally, overexpression of ABCC3 in colon cancer cells conferred resistance to anticancer drug-induced cytotoxicity. Our data thus suggest that Wnt signaling represses ABCC3 expression during colon carcinogenesis, and that subsequent upregulation of ABCC3 expression during drug treatment might contribute to acquired drug resistance.