title: MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms.
abstract: MUC4 mucin is a high molecular weight transmembrane glycoprotein that plays important roles in tumour biology. It is aberrantly expressed in pancreatic adenocarcinoma, while not being detectable in the normal pancreas. Previous studies have demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in CF, is implicated in multiple cellular functions, including gene regulation. In the present study, using a CFTR-defective pancreatic cancer cell line and its derived subline expressing functional CFTR, we report that MUC4 expression is negatively regulated by CFTR. Short-interfering RNA (siRNA)-mediated silencing of CFTR also leads to an increased expression of MUC4. Additionally, our results suggest that CFTR-mediated regulation of MUC4 is cell density-dependent and is achieved by transcriptional and posttranslational mechanisms. Moreover, in a panel of pancreatic cancer cell lines and normal pancreas, we observed that CFTR was downregulated in pancreatic cancer cells and negatively correlated with MUC4 in most cases. An aberrant expression of MUC4 was also detected in the CF pancreas. Downregulation of CFTR in pancreatic adenocarcinoma and its inverse association with the tumour-linked mucin, MUC4, indicate novel function(s) of CFTR in pancreatic tumour biology and suggest the implication of new signalling pathway(s) in MUC4 regulation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Singh
authors.forename: S C
authors.initials: SC
authors.lastname: Chauhan
authors.forename: M
authors.initials: M
authors.lastname: Andrianifahanana
authors.forename: N
authors.initials: N
authors.lastname: Moniaux
authors.forename: J L
authors.initials: JL
authors.lastname: Meza
authors.forename: M C
authors.initials: MC
authors.lastname: Copin
authors.forename: I
authors.initials: I
authors.lastname: van Seuningen
authors.forename: M A
authors.initials: MA
authors.lastname: Hollingsworth
authors.forename: J P
authors.initials: JP
authors.lastname: Aubert
authors.forename: S K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D017931:DNA Primers; D006801:Humans; D055264:Mucin-4; D009077:Mucins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C524658:MUC4 protein, human; D055264:Mucin-4; D009077:Mucins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019005:Cystic Fibrosis Transmembrane Conductance Regulator