Somatic polyploidy is associated with the upregulation of c-MYC interacting genes and EMT-like signature

Abstract

The dependence of cancer on overexpressed c-MYC and its predisposition for polyploidy represents a double puzzle. We address this conundrum by cross-species transcription analysis of c-MYC interacting genes in polyploid vs. diploid tissues and cells, including human vs. mouse heart, mouse vs. human liver and purified 4n vs. 2n mouse decidua cells. Gene-by-gene transcriptome comparison and principal component analysis indicated that c-MYC interactants are significantly overrepresented among ploidy-associated genes. Protein interaction networks and gene module analysis revealed that the most upregulated genes relate to growth, stress response, proliferation, stemness and unicellularity, as well as to the pathways of cancer supported by MAPK and RAS coordinated pathways. A surprising feature was the up-regulation of epithelial-mesenchymal transition (EMT) modules embodied by the N-cadherin pathway and EMT regulators from SNAIL and TWIST families. Metabolic pathway analysis also revealed the EMT-linked features, such as global proteome remodeling, oxidative stress, DNA repair and Warburg-like energy metabolism. Genes associated with apoptosis, immunity, energy demand and tumour suppression were mostly down-regulated. Noteworthy, despite the association between polyploidy and ample features of cancer, polyploidy does not trigger it. Possibly it occurs because normal polyploidy does not go that far in embryonalisation and linked genome destabilisation. In general, the analysis of polyploid transcriptome explained the evolutionary relation of c-MYC and polyploidy to cancer.

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics

“…This extreme endurance of tumour cells is likely borrowed from the phylogenetic evolution of cell response to stress [136,137], where the elastic epigenetic reprogramming was the main tool in the search of the available survival pathways. In this reprogramming, the protozoan, and even prokaryotic transcription cassettes (in the latter, first of all, of the DNA repair pathways), become dominating in the transcriptome of cancer gene network [138][139][140][141][142], particularly in association with polyploidy [143,144]. Accordingly, cancer is not only reprogrammed to the expression state of a gamete, a two-cell embryo or morula of a multicellular organism [100,113], but it can recapitulate through reprogramming the adaptive pathways of unicellular organisms.…”

Accelerated Senescence of Cancer Stem Cells: A Failure to Thrive or a Route to Survival?

“…More likely, these tumor cells exploit the life-cycle-like regulations of the unicellular organisms recapitulated from evolutionary ploidy cycles as we have postulated previously in Refs. [70,71] and showed recently by bioinformatics study of polyploidy [72]. It only remains to add that in general tumor cells cannot bear wild type TP53 and inactivate it, if not by mutations, then in many other ways [73].…”

Natural killer cell activity irreversibly decreases after Cryptosporidium gastroenteritis in neonatal mice

“…The goal of the study was to investigate the postponed effects of neonatal Cryptosporidium gastroenteritis on C3HA mice innate immunity and growth. The interest to this problem was fuelled by the studies indicating that neonatal cryptosporidiosis may trigger hyperpolyploid cardiomyopathy, hepatopathy, and malignancy in rodents [32][33][34][35] and by the data confirming that the immune system impairment plays a key role in the development of these diseases. [36][37][38] Currently, the nature of the relationships between cryptosporidiosis and the immune system state of the infected animal remains poorly understood.…”