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SOS1 promotes epithelial-mesenchymal transition of Epithelial Ovarian Cancer(EOC) cells through AKT independent NF-κB signaling pathway.

ABSTRACT: We aimed to explore the role and mechanism of SOS1 (Son of sevenless homolog 1) in malignant behaviors of epithelial ovarian cancer (EOC) cells Hey with high metastatic potential. Firstly, compared with Hey-WT (wild type) and Hey-NT (none targeted) cells, Hey-SOS1i cells showed decreased polarities, disorders in cytoskeleton arrangement. Numbers of transwell migrated, invaded, intravasation cells and extravasated cells were decreased significantly. Hey-NT cells and Hey-SOS1i cells were employed to establish a peritoneal dissemination model in nude mice. Hey-SOS1i cells formed less implantation metastatic foci in the abdominal cavity than Hey-NT cells, especially on the intestine and diaphragm in the 5^th week after the tumor cells were injected intraperitoneally. SOS1 knockdown in Hey cells resulted in increased E-cadherin and decreased Vimentin, N-cadherin, MMP2, and MMP9, together with reduced Snail and activation of NF-κB pathway. Together, these results suggest SOS1 might induce EMT through activating AKT independent NF-κB pathway and the transcriptive activity of Snail, and subsequently regulate the cytoskeleton reprogramming and cell motility of Hey, one of EOC cells with high metastatic potential. This may provide some new targets for the treatment of ovarian cancer with high metastatic potential.

SUBMITTER: Cheng M

PROVIDER: S-EPMC8242062 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In epithelial ovarian cancer (EOC), acquisition of invasiveness is accompanied by the loss of the epithelial features and the gain of a mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT). Understanding the regulation of cell behavior during EMT is crucial for identifying the molecular mechanisms of EOC dissemination. Previously we identified the mannose receptor LY75 as the cellular phenotype modulator. LY75 suppression induces the mesenchymal to epithelial transition (MET) in EOC cell lines with mesenchymal phenotype. In this study, we used the Reduced Representation Bisulfite Sequencing (RRBS) technology for a comprehensive analysis of DNA methylation alterations during LY75-mediated EMT in EOC cells. Three different comparison (M vs E) combinations were used for RRBS analysis, as further analysis of the sequencing data based on differentially methylated regions (DMRs) covering genes’ exons and promoter regions was indicative for about 10,000 genes displaying DMRs for each of the three experimental combinations. Consecutive Venn diagram analysis of the DMRs data from the of the three experimental combinations revealed 6666 genes, displaying common altered DMRs in their exons/promoter regions, following LY75-mediated EMT alterations in EOC cells. Based on the 6666 gene list, we further proceeded with a more stringent selection of genes displaying rather high degree (>70%) of methylation in their promoter regions and previously shown to be implicated in cancer-related EMT signaling. Our stringent selection retained 45 genes (see Supplemental Table 1E), as the DNA methylation status of the promoter regions of most of these genes was further validated by an alternative approach (BSP sequencing). Ten genes were finally selected, whose promoter DNA methylation pattern coincided with their mRNA and protein expression levels. Further in vitro and in vivo studies are warranted to more completely elucidate the functional implications of these 10 genes in ovarian tumorigenesis.

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SOS1 promotes epithelial-mesenchymal transition of Epithelial Ovarian Cancer(EOC) cells through AKT independent NF-κB signaling pathway.

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