Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1{alpha}
Résumé
MUC4 is a membrane-bound mucin overexpressed in the early steps of oesophageal carcinogenesis and implicated in tumour progression. We previously showed that bile acids, main components of gastro-oesophageal reflux and tumour promoters, upregulate MUC4 expression. HNF1{alpha} and HNF4{alpha} transcription factors are known to mediate bile acids effects, and we previously identified cis-elements for these factors in MUC4 distal promoter. Our aim was to demonstrate that these two transcription factors were directly involved in MUC4 activation by bile acids. MUC4, HNF1{alpha} and HNF4{alpha} expression was evaluated by immunohistochemistry in human oesophageal tissues. Our results indicate that MUC4, HNF1{alpha} and HNF4{alpha} were co-expressed in oesophageal metaplastic and adenocarcinomatous tissues. Studies at the mRNA, promoter and protein levels indicated that HNF1{alpha} regulates endogenous MUC4 expression by binding to two cognate cis-elements respectively located at -3332/-3327 and -3040/-3028 in the distal promoter. We also showed by siRNA approach, co-transfection and site-directed mutagenesis that HNF1{alpha} mediates taurodeoxycholic and taurochenodeoxycholic bile acids activation of endogenous MUC4 expression and transcription in a dose-dependent manner. In conclusion, these results describe a new mechanism of regulation of MUC4 expression by bile acids, in which HNF1{alpha} is a key mediator. These results bring new insights in MUC4 up-regulation in oesophageal carcinoma associated with bile reflux.
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