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

被引：32

作者：

Xie, Chen ^{[1
]}

Subhash, Vinod Vijay ^{[1
,2
]}

Datta, Arpita ^{[3
]}

Liem, Natalia ^{[1
]}

Tan, Shi Hui ^{[1
]}

Yeo, Mei Shi ^{[1
]}

Tan, Woei Loon ^{[1
]}

Koh, Vivien ^{[1
]}

Yan, Fui Leng ^{[1
]}

Wong, Foong Ying ^{[1
]}

Wong, Wai Keong ^{[4
,5
]}

So, Jimmy ^{[6
,7
]}

Tan, Iain Beehuat ^{[8
]}

Padmanabhan, Nisha ^{[10
]}

Yap, Celestial T. ^{[3
,9
]}

Tan, Patrick ^{[10
]}

Goh, Liang Kee ^{[11
]}

Yong, Wei Peng ^{[1
,2
]}

机构：

[1] Natl Univ Singapore Hosp, Dept Haematol Oncol, Level 7,NUHS Tower Block,1E,Kent Ridge Rd, Singapore 119228, Singapore

[2] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore

[3] Natl Univ Singapore, Dept Physiol, Singapore 117548, Singapore

[4] Singapore Gen Hosp, Dept Pathol, Singapore, Singapore

[5] Singapore Gen Hosp, Dept Gen Surg, Singapore, Singapore

[6] Natl Univ Hlth Syst, Dept Med, Dept Surg, Singapore, Singapore

[7] Natl Univ Hlth Syst, Dept Pathol, Singapore, Singapore

[8] Natl Canc Ctr Singapore, Dept Med Oncol, Singapore, Singapore

[9] Natl Univ Singapore, Inst Canc, Singapore 117548, Singapore

[10] Duke NUS Grad Med Sch, Dept Canc & Stem Cell Biol, Singapore, Singapore

[11] Duke NUS Grad Med Sch, Ctr Quantitat Med, Singapore, Singapore

来源：

CELLULAR ONCOLOGY | 2016年 / 39卷 / 02期

关键词：

MAGE-A3; Methylation; Proliferation; Apoptosis; Docetaxel; Gastric cancer; MAGE-A; CANCER/TESTIS ANTIGENS; TRANSCRIPTION FACTOR; INDUCED APOPTOSIS; MYELOMA CELLS; GENE FAMILY; EXPRESSION; SURVIVIN; P53; LINES;

D O I：

10.1007/s13402-015-0261-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. 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. Clinical analysis of 223 primary patient-derived samples (n(tumor) = 161, n(normal) = 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. 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.

引用

页码：175 / 186

页数：12

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