Identification of Ovarian Cancer Metastatic miRNAs

Abstract

Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2–4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.

Expression of miR-146a in patients with ovarian cancer and its clinical significance

“…It was demonstrated that high miR-146a expression was able to induce the formation of spheroids from cancer cells in vitro. This process mimics the in vivo intraperitoneal dissemination of cancer cell conglomerates over peritoneal cavities to form metastases (27).…”

“…Similarly, Cui et al (31) detected downregulation of miR-146a in OVCAR3, CAOV3 and HEY ovarian cancer epithelial cells compared with HOSE cells. To the best of our knowledge, the only previous published study investigating the differences between ovarian primary tumor and metastases in the context of miR expression levels, was performed by Vang et al (27) on 9 paired tissue specimens of primary lesions and omental metastases in serous cancer: Vang et al (27) demonstrated that miR-146a expression level was increased in metastases compared with in primary lesion tissues. It was demonstrated that high miR-146a expression was able to induce the formation of spheroids from cancer cells in vitro.…”

“…Analysis of miR-484 revealed that the chemosensitive tumor phenotype was induced by modulation of vascular endothelial growth factor (VEGF) B and VEGFR2 signaling pathways (25). Another possible mechanism underlying chemoresistance may be dependent on miR-146a and miR-150 (27). The expression levels of miR-146a and miR-150 were studied in SKOV-3, OVCAR-8 and IGROV-1 cell lines, and it was demonstrated that increased platinum tolerance was associated with spheroid formation, a model of peritoneal spread of cancer cells (27).…”

“…Another possible mechanism underlying chemoresistance may be dependent on miR-146a and miR-150 (27). The expression levels of miR-146a and miR-150 were studied in SKOV-3, OVCAR-8 and IGROV-1 cell lines, and it was demonstrated that increased platinum tolerance was associated with spheroid formation, a model of peritoneal spread of cancer cells (27). Additionally, it was revealed that spheroid formation correlated with elevated miR-146a expression in metastases (27), contrary to the results of the present study.…”

“…In vitro and in vivo studies have suggested that the pattern of miR expression may have an impact on the chemosensitivity of ovarian tumors (23)(24)(25)(26). Vang et al (27) performed a study on a small group of patients with advanced ovarian serous cancer: The study revealed dysregulation of miR-146a and miR-150 in omental metastases and suggested their possible role in increased platinum tolerance (27).…”