Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas.
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.
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.|Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.|Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
Seiya
S
Yokoyama
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.|Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Michiyo
M
Higashi
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Sho
S
Kitamoto
Department of General and Visceral Surgery, University of Ulm, Ulm, Germany.
Monika
M
Oeldorf
Department of General and Visceral Surgery, University of Ulm, Ulm, Germany.
Uwe
U
Knippschild
Department of General and Visceral Surgery, University of Ulm, Ulm, Germany.
Marko
M
Kornmann
Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.|Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan.
Kosei
K
Maemura
Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan.
Hiroshi
H
Kurahara
Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
Edwin
E
Wiest
Department of Oral Surgery, Kagoshima University Medical and Dental Hospital, Kagoshima, Japan.
Tomofumi
T
Hamada
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Ikumi
I
Kitazono
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Yuko
Y
Goto
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Takashi
T
Tasaki
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Tsubasa
T
Hiraki
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Kazuhito
K
Hatanaka
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Yuko
Y
Mataki
Department of Digestive and Life-Style Related Diseases, Human and Environmental Sciences, Health Research, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Hiroki
H
Taguchi
Department of Digestive and Life-Style Related Diseases, Human and Environmental Sciences, Health Research, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Shinichi
S
Hashimoto
Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Surinder K
SK
Batra
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Akihide
A
Tanimoto
Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.
Suguru
S
Yonezawa
Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
Michael A
MA
Hollingsworth
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018938:Caco-2 Cells; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008745:Methylation; D008875:Middle Aged; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D055264:Mucin-4 / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012044:Regression Analysis; D012307:Risk Factors
D014408:Biomarkers, Tumor; C060192:MUC1 protein, human; C524658:MUC4 protein, human; D018396:Mucin-1; D055264:Mucin-4
DNA methylation; PDAC; mucin; pancreas; prognosis