Epigenetic regulation and role of metastasis suppressor genes in pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is distinguished by rapid dissemination. Thus, genetic and/or epigenetic deregulation of metastasis suppressor genes (MSG) is a likely event during early pancreatic carcinogenesis and a potential diagnostic marker for the disease. We investigated 9...

Authors: Mardin, Wolf Arif Mithat
Haier, Jörg
Mees, Sören Torge
Division/Institute:FB 05: Medizinische Fakultät
Document types:Article
Media types:Text
Publication date:2013
Date of publication on miami:21.02.2014
Modification date:16.04.2019
Edition statement:[Electronic ed.]
Source:BMC Cancer 13 (2013) 264
Subjects:Pancreatic ductal adenocarcinoma; PDAC; Metastasis suppressor gene; Methylation; Epigenetics; Promoter
DDC Subject:610: Medizin und Gesundheit
License:CC BY 2.0
Language:English
Notes:Finanziert durch den Open-Access-Publikationsfonds 2013/2014 der Deutschen Forschungsgemeinschaft (DFG) und der Westfälischen Wilhelms-Universität Münster (WWU Münster).
Format:PDF document
URN:urn:nbn:de:hbz:6-24319434534
Permalink:http://nbn-resolving.de/urn:nbn:de:hbz:6-24319434534
Other Identifiers:DOI: 10.1186/1471-2407-13-264
Digital documents:1471-2407-13-264.pdf

Background: Pancreatic ductal adenocarcinoma (PDAC) is distinguished by rapid dissemination. Thus, genetic and/or epigenetic deregulation of metastasis suppressor genes (MSG) is a likely event during early pancreatic carcinogenesis and a potential diagnostic marker for the disease. We investigated 9 known MSGs for their role in the dissemination of PDAC and examined their promoters for methylation and its use in PDAC detection. Methods: MRNA expression of 9 MSGs was determined in 18 PDAC cell lines by quantitative RT-PCR and promoter methylation was analyzed by Methylation Specific PCR and validated by Bisulfite Sequencing PCR. These data were compared to the cell lines’ in vivo metastatic and invasive potential that had been previously established. Statistical analysis was performed with SPSS 20 using 2-tailed Spearman’s correlation with P < 0.05 being considered significant. Results: Complete downregulation of MSG-mRNA expression in PDAC cell lines vs. normal pancreatic RNA occurred in only 1 of 9 investigated genes. 3 MSGs (CDH1, TIMP3 and KiSS-1) were significantly methylated. Methylation only correlated to loss of mRNA expression in CDH1 (P < 0.05). Bisulfite Sequencing PCR showed distinct methylation patterns, termed constant and variable methylation, which could distinguish methylation-regulated from non methylation-regulated genes. Higher MSG mRNA-expression did not correlate to less aggressive PDAC-phenotypes (P > 0.14). Conclusions: Genes with metastasis suppressing functions in other tumor entities did not show evidence of assuming the same role in PDAC. Inactivation of MSGs by promoter methylation was an infrequent event and unsuitable as a diagnostic marker of PDAC. A distinct methylation pattern was identified, that resulted in reduced mRNA expression in all cases. Thus, constant methylation patterns could predict regulatory significance of a promoter’s methylation prior to expression analysis and hence present an additional tool during target gene selection.