Abstract
Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies.
Highlights
In normal cells, genomic stability is maintained by multiple highly controlled mechanisms that secure fidelity of DNA replication during S phase, segregation of chromosomes during mitosis, and precise repair of DNA damage throughout the cell cycle [1]
Aurora Kinase C (AURKC) expression is largely limited to cells that undergo meiosis, as shown in both human cells and mouse models [69,70], unlike its closely related family members, Aurora Kinase A (AURKA) and Aurora Kinase B (AURKB), which are expressed in mitotic cells [110]
Exploring how cancer cells regulate genomic instability is highly relevant to our understanding of cancer development
Summary
Genomic stability is maintained by multiple highly controlled mechanisms that secure fidelity of DNA replication during S phase, segregation of chromosomes during mitosis, and precise repair of DNA damage throughout the cell cycle [1]. The development of high-throughput techniques for DNA sequencing has enabled large-scale analysis of cancer genomes to identify common and rare genomic alterations that may support tumorigenesis. As expected, such genomic changes often involve genes encoding tumor suppressors or proto-oncogenes. Due to their restricted expression pattern and immunogenic properties, cancer/testis antigens have attracted a lot of attention as potential therapeutic targets These testes germ cell proteins participate in specialized processes of spermatogenesis, which include sustaining a pool of highly proliferative spermatogonial stem cells and several stages of cellular differentiation into mature sperm. Recent evidence suggests that ectopic expression of testis germ cell proteins in somatic cells, especially meiosis proteins, can interfere with genomic stability and promote tumorigenesis
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