Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas
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Seiya Yokoyama1,2,3, Michiyo Higashi1,2, Sho Kitamoto1, Monika Oeldorf4, Uwe Knippschild4, Marko Kornmann4, Kosei Maemura2,5, Hiroshi Kurahara5, Edwin Wiest3, Tomofumi Hamada6, Ikumi Kitazono1, Yuko Goto1, Takashi Tasaki1, Tsubasa Hiraki1, Kazuhito Hatanaka1, Yuko Mataki1, Hiroki Taguchi7, Shinichi Hashimoto7, Surinder K. Batra8, Akihide Tanimoto1, Suguru Yonezawa1, Michael A. Hollingsworth3
1Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
2Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
3Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
4Department of General and Visceral Surgery, University of Ulm, Ulm, Germany
5Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
6Department of Oral Surgery, Kagoshima University Medical and Dental Hospital, Kagoshima, Japan
7Department of Digestive and Life-Style Related Diseases, Human and Environmental Sciences, Health Research, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
8Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
Michiyo Higashi, email: [email protected]
Keywords: pancreas, prognosis, DNA methylation, mucin, PDAC
Received: March 08, 2016 Accepted: May 01, 2016 Published: June 08, 2016
Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.
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