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Bile acids induce MUC2 overexpression in human colon carcinoma cells.

Song S, Byrd JC, Koo JS, Bresalier RS

Department of Gastrointestinal Medicine and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.

BACKGROUND: Mucin alterations are a common feature of colonic neoplasia, and alterations in MUC2 mucin have been associated with tumor progression in the colon. Bile acids have been linked to colorectal carcinogenesis and mucin secretion, but their effects on mucin gene expression in human colon carcinoma cells is unknown METHODS: Human colon carcinoma cells were treated </= 6 hours with 10-200 microM deoxycholate, chenodeoxycholate, or ursodeoxycholate. MUC2 protein was assayed by Western blot analysis and MUC2 transcription was assayed using a MUC2 promoter reporter luciferase construct. Transcription activator protein 1 (AP-1) activity was measured using an AP-1 reporter construct and confirmed by Western blot analysis for c-Jun/AP-1. RESULTS: MUC2 transcription and MUC2 protein expression were increased three to fourfold by bile acids in a time and dose-dependent manner with no effect on cell viability. AP-1 activity was also increased (deoxycholate > chenodeoxycholate > ursodeoxycholate). Treatment with the putative chemopreventive agent curcumin, which decreased AP-1 activity, also decreased MUC2 transcription. Cotransfection with a dominant negative AP-1 vector decreased MUC2 transcription, confirming the significance of AP-1 in MUC2 induction by deoxycholate. Calphostin C, a specific inhibitor of protein kinase C (PKC), greatly decreased bile acid-induced MUC2 transcription and AP-1 activity, whereas inhibitors of MAP kinase had no effect. CONCLUSIONS: Bile acids induced mucin expression in human colon carcinoma cells by increasing MUC2 transcription through a process involving MAP kinase-independent, PKC-dependent activation of AP-1.

Published 13 April 2005 in Cancer, 103(8): 1606-14.
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