MPP3 inactivation by promoter CpG islands hypermethylation in colorectal carcinogenesis

Article type: Research Article

Authors: Feng, Xiao^{a; 1} | Chen, Kequan^{b; 1} | Ye, Shicai^a | Wang, Hao^a | Wei, Guoli^a | Tan, Wenkai^a | Cheng, Si^a | Zhang, Yali^c | Liu, Side^{c; *} | Zhou, Yu^{a; *}

Affiliations: [a] Department of Gastroenterology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong, China | [b] Department of Gastroenterology, the First Affiliated Hospital of Guangzhou Medical College, Guangzhou, Guangdong, China | [c] Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

Correspondence: [*] The two corresponding authors contributed equally. Corresponding authors: Side Liu, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Tonghe road1838, Guangzhou, China. Tel.: +86 13902212459; E-mail: liuside@163.com; Yu Zhou, Department of Gastroenterology, The affiliated Hospital of Guangdong Medical College, Xiashan District, South Peoples Avenue No. 57 Zhanjiang, China. Tel.: +86 13560531233; Fax: +86 0759 2369666; E-mail: ahdg2005@126.com E-mail: liuside@163.com; Yu Zhou, Department of Gastroenterology, The affiliated Hospital of Guangdong Medical College, Xiashan District, South Peoples Avenue No. 57 Zhanjiang, China. Tel.: +86 13560531233; Fax: +86 0759 2369666; E-mail: ahdg2005@126.com.

Note: [1] The first two authors contributed equally.

Abstract: Background:The Drosophila discs large tumor suppressor homologue-3 (MPP3), a putative tumor suppressor involved in cell adhesion and cell polarity, is frequently inactivated in several carcinomas due to promoter hypermethylation. The alteration of MPP3 methylation in colorectal carcinogenesis has not been investigated. Objective:To determine the role of inactivated MPP3 in colorectal tumorigenesis and the potential clinical application as a novel epigenetic marker. Methods:We measured MPP3 mRNA expression and promoter methylation in 6 colorectal cancer cell lines, 23 primary colorectal carcinomas and corresponding non-cancerous tissues. The correlations between MPP3 expression, DNA methylation and clinicopathological characteristics were evaluated. Results:Loss of MPP3 expression was observed in 2 of 6 (33.3%) colorectal cancer cell lines and 10 of 23 (43.5%) primary colorectal carcinomas. MPP3 promoter hypermethylation also occurred in the same colorectal cancer cell lines (SW1116 and LoVo) and 9 of 23 (39.1%) primary colorectal carcinomas. Among tumors loss of MPP3 mRNA expression, the promoter hypermethylation rate was 80%, which was significantly higher than tumors with over-expressed MPP3 (7.7%, P=0.001). After treated with 5-aza-dC, two cell lines (SW1116 and LoVo) revealed significant restoration of MPP3 expression. MPP3 promoter methylation was also significantly higher in advanced colorectal carcinoma (57.1%) compared with early stage tumor (11.1%). Conclusion:These preliminary data suggested that epigenetic inactivation of MPP3 frequently occurred during the development of colorectal cancer and might also be a potential biomarker for molecular classification of colorectal cancer patients.

Keywords: Tumor suppressor gene, MPP3, methylation, colorectal cancer

DOI: 10.3233/CBM-2012-0264

Journal: Cancer Biomarkers, vol. 11, no. 2-3, pp. 99-106, 2012