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. 2017 Mar;13(3):1609-1618.
doi: 10.3892/ol.2017.5665. Epub 2017 Feb 1.

Expression and prognostic relevance of MAGE-A3 and MAGE-C2 in non-small cell lung cancer

Xinfeng Chen  1   2 , Liping Wang  1   2 , Jinyan Liu  1 , Lan Huang  1   2 , Li Yang  1   2 , Qun Gao  1   2 , Xiaojuan Shi  1   2 , Jieyao Li  1   2 , Feng Li  1   2 , Zhen Zhang  1 , Song Zhao  3 , Bin Zhang  4 , Pierre Van der Bruggen  5 , Yi Zhang  1   2   6   7
Affiliations

Expression and prognostic relevance of MAGE-A3 and MAGE-C2 in non-small cell lung cancer

Xinfeng Chen et al. Oncol Lett. 2017 Mar.

Abstract

Melanoma-associated antigen (MAGE)-A3 and MAGE-C2 are antigens encoded by cancer-germline genes, and have been recognized as potential prognostic biomarkers and attractive targets for immunotherapy in multiple types of cancer. The present study aimed to analyze the clinicopathological significance of MAGE-A3/C2 expression in non-small cell lung cancer (NSCLC). The association between MAGE-A3/C2 mRNA and protein expression, and the pathological characteristics and overall survival of patients with NSCLC was analyzed. In addition, the functional role of MAGE-A3 in human NSCLC cell line A549 was examined in vitro. MAGE-A3/C2 mRNA expression was identified in 73% (151/206) and 53% (109/206) of patients with NSCLC, respectively. MAGE-A3/C2 protein expression was identified in 58% (44/76) and 53% (40/76) of NSCLC cases, respectively. MAGE-A3 mRNA expression was observed to be associated with smoking history, disease stage and lymph node metastasis. However, no association was identified between MAGE-C2 mRNA expression and the clinicopathological characteristics of patients with NSCLC. MAGE-A3/C2-positive patients had a poorer survival rate compared with MAGE-A3/C2-negative patients. Multivariate analysis identified that MAGE-A3 expression may serve as an independent marker of poor prognosis in patients with NSCLC. Downregulation of MAGE-A3 mRNA expression in A549 cells resulted in lower migration and colony formation rates, and a higher amount of epithelial marker and lower amount of mesenchymal marker expression compared with the control group. These results indicate that MAGE-A3 serves a role in NSCLC cell metastasis through the induction of epithelial-mesenchymal transition. In conclusion, MAGE-A3 may serve as a diagnostic and prognostic biomarker for patients with NSCLC, due to its association with tumor progression and poor clinical outcome.

Keywords: cancer-germline genes; epithelial-mesenchymal transition; non-small cell lung cancer; prognostic biomarker.

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Figures

Figure 1.
Figure 1.
Representative mRNA and protein expression of MAGE-A3/C2 in NSCLC tissues. (A) Agarose gel electrophoresis of reverse transcription polymerase chain reaction results for MAGE-A3/C2 mRNA expression in NSCLC samples. GAPDH was used as an internal control. Lanes: M, marker; 1, normal testis tissue used as a positive control; 2, healthy lung tissue; 3–10, NSCLC tissues. (B) Immunohistochemical analysis of MAGE-A3/C2 protein expression in NSCLC specimens. (B) Tumor staining with monoclonal antibodies against MAGE-A3/C2. a, MAGE-A3 positive normal testis sample (positive control); b, MAGE-A3-positive NSCLC sample; c, MAGE-A3-negative NSCLC sample; d, MAGE-C2-positive normal testis sample (positive control); e, MAGE-C2-positive NSCLC samples; f, MAGE-C2-negative NSCLC sample. Magnification, ×200. MAGE, melanoma-associated antigen; NSCLC, non-small cell lung cancer; bp, base pairs.
Figure 2.
Figure 2.
Kaplan-Meier estimator overall survival curves for patients with NSCLC. Overall survival of patients with NSCLC who underwent surgical resection based on expression of (A) MAGE-A3, (B) MAGE-C2 and (C) MAGE-A3 and MAGE-C2. MAGE, melanoma-associated antigen; NSCLC, non-small cell lung cancer.
Figure 3.
Figure 3.
Effect of MAGE-A3 knockdown on A549 cells. (A) Evaluation of efficiency of si-mediated MAGE-A3 knockdown via qRT-PCR analysis. (B) Effect of MAGE-A3 knockdown on cell apoptosis was detected through flow cytometry and quantified. (C) Depletion of MAGE-A3 inhibited cell colony formation. (D) Representative distinction of migration in A549 cells treated by scrambled and specific MAGE-A3 siRNA. (E) Downregulation of MAGE-A3 in A549 cells resulted in reduced cell migration. (F) Effect of MAGE-A3 knockdown on the expression of epithelial-mesenchymal transition markers was detected by qRT-PCR. All experiments were repeated ≥3 times. Data were compared using paired two-tailed t-tests. *P<0.05, **P<0.01, ***P<0.001 vs. the scrambled control group. MAGE, melanoma-associated antigen; si, small interfering RNA; EMT, epithelial-mesenchymal-transition marker; E-cad, epithelial-cadherin; N-cad, neural-cadherin; SLUG, snail family transcriptional repressor 2; Vim, vimentin; bp, base pairs; qPCR, quantitative polymerase chain reaction.
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