Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal gastro-oesophageal reflux and bile acids have been linked to the presence of Barrett's oesophageal premalignant lesion associated with an increase in mucin-producing goblet cells and MUC4 mucin gene overexpression. However, the molecular mechanisms underlying the regulation of MUC4 by bile acids are unknown. Since total bile is a complex mixture, we undertook to identify which bile acids are responsible for MUC4 up-regulation by using a wide panel of bile acids and their conjugates. MUC4 apomucin expression was studied by immunohistochemistry both in patient biopsies and OE33 oesophageal cancer cell line. MUC4 mRNA levels and promoter regulation were studied by reverse transcriptase-PCR and transient transfection assays respectively. We show that among the bile acids tested, taurocholic, taurodeoxycholic, taurochenodeoxycholic and glycocholic acids and sodium glycocholate are strong activators of MUC4 expression and that this regulation occurs at the transcriptional level. By using specific pharmacological inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase A and protein kinase C, we demonstrate that bile acid-mediated up-regulation of MUC4 is promoter-specific and mainly involves activation of phosphatidylinositol 3-kinase. This new mechanism of regulation of MUC4 mucin gene points out an important role for bile acids as key molecules in targeting MUC4 overexpression in early stages of oesophageal carcinogenesis.
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PMID:Transcriptional regulation of human mucin MUC4 by bile acids in oesophageal cancer cells is promoter-dependent and involves activation of the phosphatidylinositol 3-kinase signalling pathway. 1458 90

MUC4 (mucin 4) 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, up-regulate MUC4 expression [Mariette, Perrais, Leteurtre, Jonckheere, Hemon, Pigny, Batra, Aubert, Triboulet and Van Seuningen (2004) Biochem. J. 377, 701-708]. HNF (hepatocyte nuclear factor) 1alpha and HNF4alpha transcription factors are known to mediate bile acid 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, HNF1alpha and HNF4alpha expressions were evaluated by immunohistochemistry in human oesophageal tissues. Our results indicate that MUC4, HNF1alpha and HNF4alpha were co-expressed in oesophageal metaplastic and adenocarcinomatous tissues. Studies at the mRNA, promoter and protein levels indicated that HNF1alpha 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 (small interfering RNA) approach, co-transfection and site-directed mutagenesis that HNF1alpha mediates taurodeoxycholic and taurochenodeoxycholic bile acid 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 HNF1alpha is a key mediator. These results bring new insights into MUC4 up-regulation in oesophageal carcinoma associated with bile reflux.
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PMID:Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. 1703 83

MUC4 is a membrane-bound mucin known to participate in tumor progression. It has been shown that MUC4 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplastic lesions to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is the gastro-esophageal reflux, and MUC4 was previously shown to be upregulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC4 plays a role in biological properties of human esophageal cancer cells. For that stable MUC4-deficient cancer cell lines (shMUC4 cells) were established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of shMUC4 cells were analyzed. Our results show that shMUC4 cells were less proliferative, had decreased migration properties and did not express S100A4 protein when compared with MUC4 expressing cells. Absence of MUC4 did not impair shMUC4 invasiveness. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC4. Altogether, these data indicate that MUC4 plays a key role in proliferative and migrating properties of esophageal cancer cells as well as is a tumor growth promoter. MUC4 mucin appears thus as a good therapeutic target to slow-down esophageal tumor progression.
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PMID:The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein. 2188 95