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. 2016 Apr;39(2):175-86.
doi: 10.1007/s13402-015-0261-5. Epub 2016 Feb 11.

Melanoma associated antigen (MAGE)-A3 promotes cell proliferation and chemotherapeutic drug resistance in gastric cancer

Chen Xie  1 , Vinod Vijay Subhash  1   2 , Arpita Datta  3 , Natalia Liem  1 , Shi Hui Tan  1   4 , Mei Shi Yeo  1 , Woei Loon Tan  1 , Vivien Koh  1 , Fui Leng Yan  1 , Foong Ying Wong  1 , Wai Keong Wong  5 , Jimmy So  6 , Iain Beehuat Tan  7 , Nisha Padmanabhan  8 , Celestial T Yap  3   9 , Patrick Tan  8 , Liang Kee Goh  4 , Wei Peng Yong  10   11
Affiliations

Melanoma associated antigen (MAGE)-A3 promotes cell proliferation and chemotherapeutic drug resistance in gastric cancer

Chen Xie et al. Cell Oncol (Dordr). 2016 Apr.

Abstract

Background: Melanoma-associated antigen (MAGE)-A3 is a member of the family of cancer-testis antigens and has been found to be epigenetically regulated and aberrantly expressed in various cancer types. It has also been found that MAGE-A3 expression may correlate with an aggressive clinical course and with chemo-resistance. The objectives of this study were to assess the relationship between MAGE-A3 promoter methylation and expression and (1) gastric cancer patient survival and (2) its functional consequences in gastric cancer-derived cells.

Methods: Samples from two independent gastric cancer cohorts (including matched non-malignant gastric samples) were included in this study. MAGE-A3 methylation and mRNA expression levels were determined by methylation-specific PCR (MSP) and quantitative real-time PCR (qPCR), respectively. MAGE-A3 expression was knocked down in MKN1 gastric cancer-derived cells using miRNAs. In addition, in vitro cell proliferation, colony formation, apoptosis, cell cycle, drug treatment, immunohistochemistry and Western blot assays were performed.

Results: Clinical analysis of 223 primary patient-derived samples (ntumor = 161, nnormal = 62) showed a significant inverse correlation between MAGE-A3 promoter methylation and expression in the cancer samples (R = -0.63, p = 5.99e-19). A lower MAGE-A3 methylation level was found to be associated with a worse patient survival (HR: 1.5, 95 % CI: 1.02-2.37, p = 0.04). In addition, we found that miRNA-mediated knockdown of MAGE-A3 expression in MKN1 cells caused a reduction in its proliferation and colony forming capacities, respectively. Under stress conditions MAGE-A3 was found to regulate the expression of Bax and p21. MAGE-A3 knock down also led to an increase in Puma and Noxa expression, thus contributing to an enhanced docetaxel sensitivity in the gastric cancer-derived cells.

Conclusions: From our results we conclude that MAGE-A3 expression is regulated epigenetically by promoter methylation, and that its expression contributes to gastric cell proliferation and drug sensitivity. This study underscores the potential implications of MAGE-A3 as a therapeutic target and prognostic marker in gastric cancer patients.

Keywords: Apoptosis; Docetaxel; Gastric cancer; MAGE-A3; Methylation; Proliferation.

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