Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas

Seiya Yokoyama, Michiyo Higashi, Sho Kitamoto, Monika Oeldorf, Uwe Knippschild, Marko Kornmann, Kosei Maemura, Hiroshi Kurahara, Edwin Wiest, Tomofumi Hamada, Ikumi Kitazono, Yuko Goto, Takashi Tasaki, Tsubasa Hiraki, Kazuhito Hatanaka, Yuko Mataki, Hiroki Taguchi, Shinichi Hashimoto, Surinder Kumar Batra, Akihide TanimotoSuguru Yonezawa, Michael A Hollingsworth

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)42553-42565
Number of pages13
JournalOncotarget
Volume7
Issue number27
DOIs
StatePublished - Jul 5 2016

Fingerprint

Methylation
Adenocarcinoma
Biomarkers
Mucins
DNA Methylation
Pancreatic Neoplasms
Survival
Genetic Promoter Regions
Epigenomics
Electrophoresis
Carcinogenesis
Molecular Weight
Carcinoma
Messenger RNA
Mortality
Genes
Neoplasms

Keywords

  • DNA methylation
  • PDAC
  • mucin
  • pancreas
  • prognosis

ASJC Scopus subject areas

  • Oncology

Cite this

Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas. / Yokoyama, Seiya; Higashi, Michiyo; Kitamoto, Sho; Oeldorf, Monika; Knippschild, Uwe; Kornmann, Marko; Maemura, Kosei; Kurahara, Hiroshi; Wiest, Edwin; Hamada, Tomofumi; Kitazono, Ikumi; Goto, Yuko; Tasaki, Takashi; Hiraki, Tsubasa; Hatanaka, Kazuhito; Mataki, Yuko; Taguchi, Hiroki; Hashimoto, Shinichi; Batra, Surinder Kumar; Tanimoto, Akihide; Yonezawa, Suguru; Hollingsworth, Michael A.

In: Oncotarget, Vol. 7, No. 27, 05.07.2016, p. 42553-42565.

Research output: Contribution to journalArticle

Yokoyama, S, Higashi, M, Kitamoto, S, Oeldorf, M, Knippschild, U, Kornmann, M, Maemura, K, Kurahara, H, Wiest, E, Hamada, T, Kitazono, I, Goto, Y, Tasaki, T, Hiraki, T, Hatanaka, K, Mataki, Y, Taguchi, H, Hashimoto, S, Batra, SK, Tanimoto, A, Yonezawa, S & Hollingsworth, MA 2016, 'Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas', Oncotarget, vol. 7, no. 27, pp. 42553-42565. https://doi.org/10.18632/oncotarget.9924
Yokoyama, Seiya ; Higashi, Michiyo ; Kitamoto, Sho ; Oeldorf, Monika ; Knippschild, Uwe ; Kornmann, Marko ; Maemura, Kosei ; Kurahara, Hiroshi ; Wiest, Edwin ; Hamada, Tomofumi ; Kitazono, Ikumi ; Goto, Yuko ; Tasaki, Takashi ; Hiraki, Tsubasa ; Hatanaka, Kazuhito ; Mataki, Yuko ; Taguchi, Hiroki ; Hashimoto, Shinichi ; Batra, Surinder Kumar ; Tanimoto, Akihide ; Yonezawa, Suguru ; Hollingsworth, Michael A. / Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas. In: Oncotarget. 2016 ; Vol. 7, No. 27. pp. 42553-42565.
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AU - Yokoyama, Seiya

AU - Higashi, Michiyo

AU - Kitamoto, Sho

AU - Oeldorf, Monika

AU - Knippschild, Uwe

AU - Kornmann, Marko

AU - Maemura, Kosei

AU - Kurahara, Hiroshi

AU - Wiest, Edwin

AU - Hamada, Tomofumi

AU - Kitazono, Ikumi

AU - Goto, Yuko

AU - Tasaki, Takashi

AU - Hiraki, Tsubasa

AU - Hatanaka, Kazuhito

AU - Mataki, Yuko

AU - Taguchi, Hiroki

AU - Hashimoto, Shinichi

AU - Batra, Surinder Kumar

AU - Tanimoto, Akihide

AU - Yonezawa, Suguru

AU - Hollingsworth, Michael A

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N2 - 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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