Abstract
Ovarian cancer is a gynecological malignancy that has a high mortality rate in women due to metastatic progression and recurrence. miRNAs are small, endogenous, noncoding RNAs that function as tumor suppressors or oncogenes in various human cancers by selectively suppressing the expression of target genes. The objective of this study is to investigate the role of miR-203 in ovarian cancer. miR-203 was expressed in ovarian cancer SKOV3 and OVCAR3 cells using lentiviral vector and cell proliferation, migration, invasion were examined using MTT, transwell and Matrigel assays, respectively. Tumor growth was examined using Xenograft mouse model. miR-203 expression was downregulated, whereas expression of its target gene Snai2 was upregulated in human ovarian serous carcinoma tissue as compared to normal ovaries. In addition, high miR-203 expression was associated with long-term survival rate of ovarian cancer patients. miR-203 overexpression inhibited cell proliferation, migration, and invasion of SKOV3 and OVCAR3 ovarian cancer cells. Furthermore, miR-203 overexpression inhibited the epithelial to mesenchymal transition (EMT) in ovarian cancer cells. Silencing Snai2 with lentiviral short hairpin (sh) RNA mimics miR-203-mediated inhibition of EMT and tumor cell invasion. Xenografts of miR-203-overexpressing ovarian cancer cells in immunodeficient mice exhibited a significantly reduced tumor growth. miR-203 functions as a tumor suppressor by down regulating Snai2 in ovarian cancer.
Highlights
Ovarian cancer has a high mortality rate, with over 20,000 new cases diagnosed and 15,000 deaths every year in the US [1]
We found that miR-203 was significantly downregulated in human ovarian carcinoma compared to normal ovary controls (Figure 1B; p = 0.034)
These findings demonstrate that miR-203 expression is positively correlated with the survival of ovarian cancer patients
Summary
Ovarian cancer has a high mortality rate, with over 20,000 new cases diagnosed and 15,000 deaths every year in the US [1]. The high mortality rate in ovarian cancer reflects late stage diagnosis, disease recurrence, and chemoresistance [2,3]. The cellular phenotypic switch from epithelial to mesenchymal cell transition (EMT) is a fundamental process in tumor initiation, progression, metastasis, and chemoresistance [48]. At initial diagnosis a late stage of metastatic progression is often observed in ovarian cancer, because of direct tumor extension and cell spreading directly through the peritoneal fluid with resultant invasion to adjacent organs [12]. The rationale is that epithelial ovarian cancer cells undergo EMT and shed tumor cells into the peritoneum, which survive as cellular aggregates or spheroids in the ascites. The spheroids attach themselves to the omentum, invade adjacent organs and undergo EMT/mesenchymal to epithelial cell transition (MET) interconversion to enhance cell proliferation and progression [16]. Signaling pathways, including WNT, Jak2/Stat, PI3 kinase/AKT, and Notch, are found to regulate EMT [19,20,21,22,23]
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