Elena Kashuba Project
Molecular mechanisms of cell transformation
Role of the Mrps18-2 Mitochondrial Protein in Control of Cell Stemness and Cancerogenesis
Our research aims to characterize novel pathways of cell fate regulation and to identify new putative diagnostic and/or prognostic markers of cancerogenesis.
S18 family of mitochondrial ribosomal proteins (MRPS18, S18) consists of three members, S18-1-3. We previously found that ectopic expression of the S18-2 protein led to the immortalization of primary rat fibroblasts, that showed an embryonic stem cell (ESC) phenotype. The S18-1 and -3 have not exhibited such abilities. To understand the differences in protein properties, the evolutionary history of S18 family was analyzed. Based on the phylogenetic analysis and the most parsimonious reconciliation between gene tree and species tree, we concluded on the ancient gene duplication and the following three rounds of the same event in Metazoa, that resulted in the three modern-day S18 proteins in metazoan species. Importantly, the evolutionarily conserved residue Gly132 in S18-2 protein shows genetic polymorphism in colon adenocarcinomas that was confirmed by direct DNA sequencing.
Terminally differentiated rat skin fibroblasts underwent transformation upon ectopic expression of the S18-2 protein. Transformed cells showed increased telomerase activity, cell cycle disturbance and chromosomal instability. We concluded that the S18-2 is an oncoprotein.
In support, we demonstrated that the S18-2 protein is expressed at high levels in endometrial cancers compared to hyperplasia and normal endometrium. Moreover, expression of S18-2 was increased with disease progression in clinical specimens of prostate cancer. The level of induction of epithelial to mesenchymal cell transition (EMT) correlated with the expression level of S18-2 in prostate cancer cell lines. Also, cells acquired increased ability of migration upon S18-2 overexpression, as was evaluated in zebrafish embryo model and in trans-well assay. We found that this is due to increased CXCR4 cell surface expression. The mRNA expression of TWIST2, encoding one of transcription factors that induce EMT upon CXCR4 increase, positively correlated with the S18-2 protein level.
Hence, the S18-2 protein induces EMT through the TWIST2/E-cadherin signaling and, consequently, CXCR4-mediated migration of cancer cells.
The International VACTRAIN/III Swedish-Ukrainian Conference on Cancer Diseases, January 16-17, 2017
The European meeting on epstein barr virus and associated malignances took place in June 2015
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