Abstract

ABSTRACTThe biological roles of cancer-testis antigens of the Melanoma antigen (Mage) family in mammalian development, stem cell differentiation and carcinogenesis are largely unknown. In order to understand the involvement of the Mage family genes in maintenance of normal and cancer stem cells, the expression patterns of Mage-a, Mage-b, Mage-d, Mage-e, Mage-h and Mage-l gene subfamilies were analyzed during the self-renewal and differentiation of mouse pluripotent stem and teratocarcinoma cells. Clustering analysis based on the gene expression profiles of undifferentiated and differentiating cell populations revealed strong correlations between Mage expression patterns and differentiation and malignant states. Gene co-expression analysis disclosed the potential contributions of Mage family members in self-renewal and differentiation of pluripotent stem and teratocarcinoma cells. Two gene clusters including Mage-a4 and Mage-a8, Mageb1, Mage-d1, Mage-d2, Mage-e1, Mage-l2 were identified as functional antagonists with opposing roles in the regulation of proliferation and differentiation of mouse pluripotent stem and teratocarcinoma cells. The identified aberrant expression patterns of Mage-a2, Mage-a6, Mage-b4, Mageb-16 and Mage-h1 in teratocarcinoma cells can be considered as specific teratocarcinoma biomarkers promoted the malignant phenotype. Our study first provides a model for the involvement of Mage family members in regulatory networks during the self-renewal and early differentiation of normal and cancerous stem cells for further research of the predicted functional modules and the development of new cancer treatment strategies.

Highlights

  • Сancer-testis antigens (CTAs) are among the most enigmatic genes in animal and human genomes because their expression patterns are highly specific, but their cell functions remain unknown

  • Melanoma antigen (Mage)-e2 is expressed at different levels in pluripotent EGCs and ESCs (p < 0.01), whereas the expression patterns of five Mage genes differs between pluripotent and teratocarcinoma cells

  • Mage-a2 and Mage-a6 are expressed at significantly higher levels in embryonic germ (EGCs) and teratocarcinoma (ECCs) F9 and Mage-a2, Mage-b4 and Mage-b16 are expressed at significantly lower levels in ECCs P19 than in pluripotent stem cells

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Summary

Introduction

Сancer-testis antigens (CTAs) are among the most enigmatic genes in animal and human genomes because their expression patterns are highly specific, but their cell functions remain unknown. Several CTA families’ members can induce spontaneous humoral and cytotoxic T-cell-mediated immune responses in cancer patients. Their immunotheraputic potential was studied in numerous clinical trials with CTA-based cancer vaccines [24,25,26]. Previous studies revealed different CTA expression patterns in normal and cancer stem cells [34, 36,37,38,39,40]. Changes www.oncotarget.com in the characteristic CTA profiles (aberrant expression) of germ and somatic cells may be associated with abnormal differentiation and cancer transformation

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