MAGE-A3 is a prognostic biomarker for poor clinical outcome in cutaneous squamous cell carcinoma with perineural invasion via modulation of cell proliferation

Abstract

Perineural invasion is a pathologic process of neoplastic dissemination along and invading into the nerves. Perineural invasion is associated with aggressive disease and a greater likelihood of poor outcomes. In this study, 3 of 9 patients with cutaneous squamous cell carcinoma and perineural invasion exhibited poor clinical outcomes. Tumors from these patients expressed high levels of MAGE-A3, a cancer testis antigen that may contribute to key processes of tumor development. In addition to perineural invasion, the tumors exhibited poor differentiation and deep invasion and were subsequently classified as Brigham and Women’s Hospital tumor stage 3. Cyclin E, A and B mRNA levels were increased in these tumors compared with normal skin tissues (102.93±15.03 vs. 27.15±4.59, 36.83±19.41 vs. 11.59±5.83, 343.77±86.49 vs. 95.65±29.25, respectively; p<0.05). A431 cutaneous squamous cell carcinoma cells pretreated with MAGE-A3 antibody exhibited a decreased percentage S-phase cells (14.13±2.8% vs. 33.97±1.1%; p<0.05) and reduced closure in scratch assays (43.88±5.49% vs. 61.17±3.97%; p = 0.0058). In a syngeneic animal model of squamous cell carcinoma, immunoblots revealed overexpression of MAGE-A3 and cyclin E, A, and B protein in tumors at 6 weeks. However, knockout of MAGE-A3 expression caused a reduction in tumor growth (mean tumor volume 155.3 mm3 vs. 3.2 mm3) compared with parental cells. These results suggest that MAGE-A3 is a key mediator in cancer progression. Moreover, elevated collagen XI and matrix metalloproteases 3, 10, 11, and 13 mRNA levels were observed in poorly differentiated cutaneous squamous cell carcinoma with perineural invasion compared with normal skin tissue (1132.56±882.7 vs. 107.62±183.62, 1118.15±1109.49 vs. 9.5±5, 2603.87±2385.26 vs. 5.29±3, 957.95±627.14 vs. 400.42±967.66, 1149.13±832.18 vs. 19.41±35.62, respectively; p<0.05). In summary, this study highlights the potential prognostic value of MAGE-A3 in clinical outcomes of cutaneous squamous cell carcinoma patients.

Expression of Cancer-testis Antigens in Adenoid Cystic Carcinoma of the Salivary Glands Correlates with Clinical Outcomes

“…Perineural invasion was present 34.3% of patients in our study, and varied widely in previous studies 25,26) . The study by Chen et al found that perineural invasion cutaneous squamous cell carcinoma was associated with increased MAGE-A3 expression 27) . The results of our study suggest that larger samples are required to interpret the role of perineural invasion in ACC.…”

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

“…Our transcriptomic analysis upon SIN3A-PF1 perturbation in 3D culture system showed significant alteration of several genes. Matrix metalloproteases proteins (MMP1 & MMP3) known enhancers of invasion and MAGEA3, CDH11, SPOCK, PTGS2 and WNT5A, overexpressed in high grade of invasive cancer, are all downregulated in PF1-SID cells [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] . LHX8 and its family member LHX6, known to inhibit breast cancer cell proliferation by repressing WNT signaling, is the topmost upregulated gene in PF1-SID cells [ 55 , 56 ].…”

The Contributions of Cancer-Testis and Developmental Genes to the Pathogenesis of Keratinocyte Carcinomas

“…Hence, MAGE-A3 expression in cSCC correlates with poor prognosis. In a follow up study, MAGE-A3 was found to be enriched in poorly-differentiated tumors with perineural invasion (PNI) relative to moderately differentiated tumors [ 69 ]. In vitro human cSCC cell lines and in vivo mouse models were used to demonstrate that MAGE-A3 may govern cell cycle progression and tumor growth in cSCC by regulating cyclin B, D and E expression, and also by promoting invasion [ 69 ].…”

“…Immunostaining for MAGE-A4 was strongest in the basal layer of the epidermis in all four tumor types [ 66 ]. Chen et al also reported that high MAGE-A4 expression was correlated with poorly differentiated cSCCs with PNI [ 69 ].…”