Browsing by Author "Salmina, Kristine"
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Item The cancer aneuploidy paradox : In the light of evolution(2019-01-01) Salmina, Kristine; Huna, Anda; Kalējs, Mārtiņš; Pjanova, Dace; Scherthan, Harry; Cragg, Mark S.; Ērenpreisa, Jekaterina; Biomehānikas zinātniskā laboratorijaAneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform the segregation of two parental groups of end-to-end linked dyads by pseudo-mitosis creating tetraploid cells through a dysfunctional spindle. This is followed by autokaryogamy and a homologous pairing preceding a bi-looped endo-prophase. The associated RAD51 and DMC1/γ- H2AX double-strand break repair foci are tandemly situated on the AURKB/REC8/kinetochore doublets along replicated chromosome loops, indicative of recombination events. MOS-associated REC8-positive peri-nucleolar centromere cluster organises a monopolar spindle. The process is completed by reduction divisions (bi-polar or by radial cytotomy including pedogamic exchanges) and by the release of secondary cells and/or the formation of an embryoid. Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle checkpoint. Concurrently, it reduces the chromosome number and facilitates recombination that decreases the mutation load of aneuploidy and lethality in the chemo-resistant tumour cells. This cancer life-cycle has parallels both within the cycling polyploidy of the asexual life cycles of ancient unicellular protists and cleavage embryos of early multicellulars, supporting the atavistic theory of cancer.Item DNA methylation of the Oct4A enhancers in embryonal carcinoma cells after etoposide treatment is associated with alternative splicing and altered pluripotency in reversibly senescent cells(2018-02-01) Bariševs, Mihails; Inashkina, Inna; Salmina, Kristine; Huna, Anda; Jackson, Thomas R.; Ērenpreisa, Jekaterina; Institute of Microbiology and VirologyThe epigenetic mechanisms underlying chemoresistance in cancer cells resulting from drug-induced reversible senescence are poorly understood. Chemoresistant ESC-like embryonal carcinoma PA1 cells treated with etoposide (ETO) were previously found to undergo prolonged G2 arrest with transient p53-dependent upregulation of opposing fate regulators, p21CIP1 (senescence) and OCT4A (self-renewal). Here we report on the analysis of the DNA methylation state of the distal enhancer (DE) and proximal enhancer (PE) of the Oct4A gene during this dual response. When compared to non–treated controls the methylation level increased from 1.3% to 12.5% and from 3% to 19.4%, in the DE and PE respectively. It included CpG and non-CpG methylation, which was not chaotic but presented two patterns in each enhancer. Discorrelating with methylation of enhancers, the transcription of Oct4A increased, however, a strong expression of the splicing form Oct4B was also induced, along with down-regulation of the Oct4A partners of in the pluripotency/self-renewal network Sox2 and Lin28. WB demonstrated disjoining of the OCT4A protein from the chromatin-bound fraction. In survival clones, methylation of the DE was considerably erased, while some remnant of methylation of the PE was still observed. The alternative splicing for Oct4B was reduced, Oct4A level insignificantly decreased, while the expression of Sox2 and Lin28 recovered, all three became proportionally above the control. These findings indicate the involvement of the transient patterned methylation of the Oct4A enhancers and alternative splicing in the adaptive regulation of cell fate choice during the p53-dependant dual state of reversible senescence in ESC-like cancer stem cells.Item The Price of Human Evolution : Cancer-Testis Antigens, the Decline in Male Fertility and the Increase in Cancer(2023-07) Ērenpreisa, Jekaterina; Vainshelbaum, Ninel Miriam; Lazovska, Marija; Kārkliņš, Roberts; Salmina, Kristine; Zayakin, Pawel; Rumnieks, Felikss; Inashkina, Inna; Pjanova, Dace; Ērenpreiss, Juris; Scientific Laboratory of Molecular GeneticsThe increasing frequency of general and particularly male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis antigens (CTA). The phylostratigraphy analysis of the human genome allowed us to link the early evolutionary origin of cancer via the reproductive life cycles of the unicellulars and early multicellulars, potentially driving soma-germ transition, female meiosis, and the parthenogenesis of polyploid giant cancer cells (PGCCs), with the expansion of the CTA multi-families, very late during their evolution. CTA adaptation was aided by retrovirus domestication in the unstable genomes of mammals, for protecting male fertility in stress conditions, particularly that of humans, as compensation for the energy consumption of a large complex brain which also exploited retrotransposition. We found that the early and late evolutionary branches of human cancer are united by the immunity-proto-placental network, which evolved in the Cambrian and shares stress regulators with the finely-tuned sex determination system. We further propose that social stress and endocrine disruption caused by environmental pollution with organic materials, which alter sex determination in male foetuses and further spermatogenesis in adults, bias the development of PGCC-parthenogenetic cancer by default.Item Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance(2022-03-01) Vainshelbaum, Ninel Miriam; Salmina, Kristine; Gerashchenko, Bogdan I.; Lazovska, Marija; Zayakin, Pawel; Cragg, Mark Steven; Pjanova, Dace; Erenpreisa, JekaterinaHere, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; p < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.Item The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction(2022-12) Vainshelbaum, Ninel M.; Giuliani, Alessandro; Salmina, Kristine; Pjanova, Dace; Ērenpreisa, JekaterinaThe expression of gametogenesis-related (GG) genes and proteins, as well as whole genome duplications (WGD), are the hallmarks of cancer related to poor prognosis. Currently, it is not clear if these hallmarks are random processes associated only with genome instability or are programmatically linked. Our goal was to elucidate this via a thorough bioinformatics analysis of 1474 GG genes in the context of WGD. We examined their association in protein–protein interaction and coexpression networks, and their phylostratigraphic profiles from publicly available patient tumour data. The results show that GG genes are upregulated in most WGD-enriched somatic cancers at the transcriptome level and reveal robust GG gene expression at the protein level, as well as the ability to associate into correlation networks and enrich the reproductive modules. GG gene phylostratigraphy displayed in WGD+ cancers an attractor of early eukaryotic origin for DNA recombination and meiosis, and one relative to oocyte maturation and embryogenesis from early multicellular organisms. The upregulation of cancer–testis genes emerging with mammalian placentation was also associated with WGD. In general, the results suggest the role of polyploidy for soma–germ transition accessing latent cancer attractors in the human genome network, which appear as pre-formed along the whole Evolution of Life.Item When Three Isn't a Crowd : A Digyny Concept for Treatment-Resistant, Near-Triploid Human Cancers(2019-07) Salmina, Kristine; Gerashchenko, Bogdan, I; Hausmann, Michael; Vainshelbaum, Ninel M.; Zayakin, Pawel; Erenpreiss, Juris; Freivalds, Talivaldis; Cragg, Mark S.; Erenpreisa, Jekaterina; Rīga Stradiņš University