Abstract
Epithelial ovarian cancer (EOC) outpaces all the other forms of the female reproductive system malignancies. MicroRNAs have emerged as promising predictive biomarkers to therapeutic treatments as their expression might characterize the tumor stage or grade. In EOC, miR-200c is considered a master regulator of oncogenes or tumor suppressors. To investigate novel miR-200c-3p target genes involved in EOC tumorigenesis, we evaluated the association between this miRNA and the mRNA expression of several potential target genes by RNA-seq data of both 46 EOC cell lines from Cancer Cell line Encyclopedia (CCLE) and 456 EOC patient bio-specimens from The Cancer Genome Atlas (TCGA). Both analyses showed a significant anticorrelation between miR-200c-3p and the protein phosphatase 3 catalytic subunit γ of calcineurin (PPP3CC) levels involved in the apoptosis pathway. Quantitative mRNA expression analysis in patient biopsies confirmed the inverse correlation between miR-200c-3p and PPP3CC levels. In vitro regulation of PPP3CC expression through miR-200c-3p and RNA interference technology led to a concomitant modulation of BCL2- and p-AKT-related pathways, suggesting the tumor suppressive role of PPP3CC in EOC. Our results suggest that inhibition of high expression of miR-200c-3p in EOC might lead to overexpression of the tumor suppressor PPP3CC and subsequent induction of apoptosis in EOC patients.
Highlights
Epithelial ovarian cancer (EOC) is the second most lethal gynecologic malignancy after cervix cancer worldwide [1]
We narrowed down the list of miR-200c-3p gene targets through the following criteria: (1) significant inverse correlation with miR-200c-3p in Cell line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA); (2) algorithm prediction of miRNA/mRNA interactions using TargetScan; (3) differential expression between tumor and normal ovarian tissues using TCGA data; and (4) enrichment analysis on the corresponding pathway annotations and check of the literature, using a PubMed search engine
To further narrow down the list of genes, inverse correlation analysis with respect to miR-200c-3p was performed across 446 TCGA OC sample tissues: 16 of the 34 genes resulted significantly anti-correlated with miR-200c-3p
Summary
Epithelial ovarian cancer (EOC) is the second most lethal gynecologic malignancy after cervix cancer worldwide [1]. Therapeutic treatment spans from surgical debulking of the affected ovaries and immunotherapy, to targeted or chemotherapy or combinatorial therapies [1,3,4,5] Despite all these treatments, worse prognosis of late diagnosed EOC patients persists and the overall survival (OS) rate is very low [6]. Calcineurin (CN) is a calcium-dependent serine/threonine phosphatase with a central function in immunity that dephosphorylates different transcription factors, such as the nuclear factor of activated T cells (NFAT), which translocate to the nucleus and regulates the expression of several target genes [13] This phosphatase is composed by a catalytic subunit (CNA), encoded by the three isoforms (PPP3CA, PPP3CB, and PPP3CC), and a regulatory subunit (CNB), encoded by two isoforms (PPP3R1 and PPP3R2). Using in silico analyses of RNA-seq data from CCLE and TCGA, we confirm a strong inverse correlation between miR-200c-3p and PPP3CC expression in EOC
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