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MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

Oncogene volume 26, pages 30–41 (2007)Cite this article

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.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

CF:

cystic fibrosis

CFTR:

cystic fibrosis transmembrane conductance regulator

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

MUC:

mucin

PanIN:

pancreatic intraepithelial neoplasm

PGK:

phosphoglycerol kinase

siRNA:

short interfering ribonucleic acid

SMC:

sialo–mucin complex

UTR:

untranslated region

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Acknowledgements

We thank Erik Moore for technical support and the Molecular Biology Core Facility for oligonucleotide synthesis and DNA sequencing. We also thank Dr Parmender Mehta (Department of Biochemistry and Molecular Biology) and Dr Rakesh Singh (Department of Pathology and Microbiology) at University of Nebraska Medical Center for critical reading of the manuscript. This work was supported, in part, by an R01 grant CA78590 from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    A P Singh, S C Chauhan, M Andrianifahanana, N Moniaux & S K Batra

  2. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    M A Hollingsworth & S K Batra

  3. Department of Preventive and Societal Medicine, Biostatistics Section, University of Nebraska Medical Center, Omaha, NE, USA

    J L Meza

  4. Unite 560 INSERM, Place de verdun, Lille Cedex, France

    M C Copin, I van Seuningen & J P Aubert

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  1. A P Singh
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  2. S C Chauhan
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  10. S K Batra
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Correspondence to S K Batra.

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Singh, A., Chauhan, S., Andrianifahanana, M. et al. MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms. Oncogene 26, 30–41 (2007). https://doi.org/10.1038/sj.onc.1209764

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