Abstract
Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2), epithelial cell-specific regulators of alternative splicing, are downregulated during the epithelial–mesenchymal transition (EMT). These factors have roles in tumor progression and metastasis in some cancers; however, their expression and function in ovarian cancer (OC) remain unclear. We found that ESRP1 and ESRP2 mRNAs were expressed at higher levels in OC cells than in immortalized ovarian surface epithelial (IOSE) cells, and confirmed their overexpression in OC tissues at the protein level. The Cancer Genome Atlas (TCGA) data analysis revealed frequent gene amplification of ESRP1 in OC tissues; however, we detected no significant correlation between ESRP1 gene copy number and gene expression in OC cells. Importantly, expression of ESRP1 and ESRP2 was inversely correlated with DNA methylation in OC cells, and ESRP2 overexpression in OC tissues was significantly associated with DNA hypomethylation. Notably, survival analysis using TCGA data from 541 OC tissues revealed that high ESRP1 expression was significantly associated with shorter 5-year survival of patients. Ectopic ESRP1 expression in mesenchymal OC cells promoted cell proliferation but suppressed cell migration. Furthermore, we found that ESRP1 drives a switch from mesenchymal to epithelial phenotype characterized by reduced cell migration in association with induction of epithelial cell-specific variant of CD44 and ENAH. Taken together, our findings suggest that an epigenetic mechanism is involved in ESRP1 overexpression, and that ESRP1 has a role in OC progression.
Highlights
We found that Epithelial splicing regulatory protein 1 (ESRP1) and ESRP2 were overexpressed in ovarian cancer (OC) tissues
This is consistent with a previous study, which describes their upregulation in human oral squamous cell carcinoma in comparison with the normal epithelium,[13] but is discordant with observations of reduced ESRP1 and ESRP2 expressions in colorectal cancer tissues.[16]
Our data demonstrated that DNA methylation is inversely correlated with both ESRP1 and ESRP2 gene expression in OC cells
Summary
Epithelial splicing regulatory proteins (ESRP1 and ESRP2) are epithelial cell-specific RNA-binding proteins that regulate alternative splicing of multiple genes, including CD44, CTNND1, ENAH and FGFR2, and participate in the epithelial–mesenchymal transition (EMT).[1,2] The EMT, which augments tumor motility and invasiveness, has a critical role in metastasis by facilitating the escape of cancer cells from primary tumors.[3,4,5] accumulating evidence indicates that the EMT promotes the emergence of cancer stem cells or tumor-initiating cells, implying that this process contributes to drug resistance and recurrence in human cancer.[6,7]. Received 7 March 2017; revised 7 July 2017; accepted 28 August 2017 in clear-cell renal cell carcinoma and breast cancer.[17] Interestingly, and ESRP2 deletion (0.9%, 5/557) in 557 OC tissues (Figure 2a, top) Another recent study analyzing TCGA RNA-sequencing data Combined analysis of copy number alteration and gene expresshowed that the expression of some ESRP2-targeted exons correlates with favorable prognosis, whereas ESRP2 expression is not associated with overall survival (OS) rate of clear-cell renal cell carcinoma patients.[12]. We detected DNA hypomethylation of CpG sites in the promoter region in OC cells expressing high levels of ESRP1 or ESRP2
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