The Melanoma-Associated Antigen A3 Mediates Fibronectin-Controlled Cancer Progression and Metastasis

Abstract

Tumor cells frequently exhibit decreased adhesiveness due to failure to deposit stromal fibronectin (FN), permitting more rapid proliferation, migration, invasion, and metastasis. Although up-regulation of FN has been noted in gene profiles of carcinomas compared with normal tissue, reduced FN expression has been described at the peripheral margins of invading tumors. In this study, we investigate the role of FN in cancer behavior. Using human thyroid carcinoma cells with stably down-regulated FN, we performed gene profiling and created an orthotopic mouse model. We stably overexpressed the FN target, MAGE A3, which has also been identified as a target of the breast cancer risk factor fibroblast growth factor receptor 2, and examined the functional effects in vitro and in vivo in a flank model and an orthotopic model of thyroid cancer. Mouse xenografts showed significantly enhanced tumor growth as well as larger and more numerous lung metastases in response to FN silencing. Gene profiling identified the melanoma-associated antigen (MAGE A3) as significantly up-regulated in response to FN silencing. Forced expression of MAGE A3 resulted in p21 down-regulation, accelerated cell cycle progression, increased cell migration rate, and invasion in vitro and in vivo in an orthotopic mouse model where microcomputed tomography confirmed lung metastases that recapitulate the progression of human thyroid cancer. We conclude that MAGE A3 is a functional integrator of diverse signals, including FGFR2 and FN, to modulate cancer progression.

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

“…Nevertheless, in the last years compelling evidence has accumulated suggesting that individual MAGE proteins could behave in specific pathways critical for tumor progression. [30][31][32][33][34] We previously demonstrated that MageA2 is a relevant player in favoring chemoresistance to p53 bearing human melanoma cells. Here, we analyze the role of MageA2 as regulator of another important tumor-suppressive mechanism, namely cellular senescence.…”

MAGE‐A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies

“…40,41 Previous studies in a thyroid carcinoma model have suggested that selected MAGE-A genes might control fibronectin-mediated tumor progression. 42 Notably, MAGE-A11, also characterized by a putatively specific intranuclear location, has been shown to coregulate androgen receptor-mediated transcriptional activity. 43,44 Most interestingly, MAGE-A gene expression has been found to be correlated with genome-wide demethylation, 45 frequently representing an early event during carcinogenesis, associated with hypermethylation of defined tumor suppressor genes.…”

Identification of Expression Signatures Predictive of Sensitivity to the Bcl-2 Family Member Inhibitor ABT-263 in Small Cell Lung Carcinoma and Leukemia/Lymphoma Cell Lines

“…Significantly, Jurkat cells, which are sensitive to ABT-263, had the highest expression of CD99 in our panel. MAGEA3 (increased in resistant leukemia/lymphoma lines) has been shown to contribute to fibronectin-mediated cancer progression through enhanced tumor growth (49).…”