Prognostic value of MAGEA4 in primary lung cancer depends on subcellular localization and p53 status

Abstract

Melanoma antigen family A4 (MAGEA4), a cancer/testis antigen, is overexpressed and is thus an immunotherapy target in various malignant tumors, including non-small cell lung cancer. However, whether MAGEA4 induces or inhibits the apoptosis of lung cancer cells remains controversial, as is its prognostic significance, particularly since there is no reliable method with which to detect MAGEA4 specifically. In this study, we optimized assay conditions to detect MAGEA4 based on cells transiently transfected with MAGEA genes, and found that MAGEA4 was expressed in four of eight non-small cell lung cancer cell lines, and in 25.4% of clinical lung cancer specimens. We also found that MAGEA4 overexpression decreased apoptosis, as measured by the levels of cleaved caspase-3 in stably transfected 293F cells. Notably, patients with nuclear MAGEA4, but not p53 expression exhibited a significantly poorer survival than those expressing both nuclear MAGEA4 and p53. Indeed, multivariate analysis identified nuclear MAGEA4 as an independent prognostic factor (P=0.0042), albeit only in the absence of p53. In this study, to the best of our knowledge, we are the first to demonstrate that the function and prognostic value of MAGEA4 depends on its subcellular localization and on the p53 status.

Systematic cancer-testis gene expression analysis identified CDCA5 as a potential therapeutic target in esophageal squamous cell carcinoma

“…Growing evidence supports MAGEA protein involvement in the regulation of the processes that underlie cancer cell survival, tumor formation, and metastasis [37,38]. For instance, MAGEA4 inhibits the apoptosis of cancer cells by suppressing endogenousp53, or by enhancing malignant progression via p53-independent pathways [39]. Simultaneously, the overexpression of TWIST1, a bHLH transcription factor, may transcriptionally up-regulate the expression of MAGEA4 to activate cancer cell migration-invasion program [40].…”

Expression of cancer–testis antigens in the immune microenvironment of non‐small cell lung cancer

“…MAGEA4 also seems to inhibit TP53‐dependent apoptosis. Furthermore, it has been demonstrated that nuclear MAGEA4 expression in the absence of nuclear TP53 expression results in poorer survival of NSCLC patients compared with cytoplasmic MAGEA4 [45]. As we did not analyze the subcellular localization of the CTAs in tumor samples, this could be one factor in why we failed to observe any difference in survival between patients with high or low CTA expression.…”

Comparative gene expression analysis in melanocytes driven by tumor cell-derived exosomes

“…Interestingly, MAGEA 4 is a cancer/testis antigen that is overexpressed in various types of malignant tumors and is an immunotherapy target. 20 Highly expressed MAGEA 4 is associated with a poor prognosis with a lower than five-year survival rate for osteosarcoma. 21 ID3 and ID1 are the other two genes that were upregulated in NHEM-c cells driven by melanoma A375exo.…”