miR-146a Inhibits Proliferation and Enhances Chemosensitivity in Epithelial Ovarian Cancer via Reduction of SOD2

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, accounting for 90% of all ovarian cancer. Dysregulation of miRNAs is associated with several types of EOC. In the current research, we aimed to study the role of abnormal expression of miR-146a in the development of EOC and to elucidate the possible molecular mechanisms. Compared with control samples, mRNA expression of miR-146a was significantly decreased in EOC tissues and cell lines. Overexpression of miR-146a prohibited cell proliferation, enhanced apoptosis, and increased sensitivity to chemotherapy drugs in EOC cells. In contrast, downregulation of miR-146a promoted cell proliferation, suppressed apoptosis, and decreased sensitivity to chemotherapy drugs in EOC cells. Overexpression of miR-146a increased the reactive oxygen species (ROS) level and decreased SOD2 mRNA and protein expression. Downregulation of miR-146a increased SOD2 mRNA and protein expression. Overexpression of SOD2 significantly inhibited miR-146a mimics-induced suppression of cell proliferation and the increase of apoptosis and chemosensitivity. In conclusion, we identify miR-146a as a potential tumor suppressor in patients with EOC. miR-146a downregulates the expression of SOD2 and enhances ROS generation, leading to increased apoptosis, inhibition of proliferation, and enhanced sensitivity to chemotherapy. The data demonstrate that the miR-146a/SOD2/ROS pathway may serve as a novel therapeutic target and prognostic marker in patients with EOC.

Protective potential of miR-146a-5p and its underlying molecular mechanism in diverse cancers: a comprehensive meta-analysis and bioinformatics analysis

“…Additionally, miR-146a-5p has been reported to function as a powerful inhibitor in cervical cancer [44]. Similar results have been obtained for epithelial ovarian cancer [45,46]. In this work, we found that elevated miR-146a-5p expression was indeed correlated with a better prognosis for patients with reproductive system cancers.…”

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

“…However, the tissue samples used in the study contained various histological types of cancer (including clear cell and endometrial cancer) and the reference samples used were cultured human ovarian surface epithelial (HOSE) cells. 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.…”

miR‐146a‐5p: Expression, regulation, and functions in cancer

“…Though the data were limited, miR‐146a expression was significantly lower in chemotherapy‐resistant patients compared to patients with partial regression or those who were in complete remission (Luo et al, ). Transfecting ovarian cancer cells with a miR‐146a mimic in tandem with paclitaxel treatment led to a more robust decrease in cell viability than with miR‐146a or paclitaxel treatment alone (Cui et al, ). Similar experiments were performed on K562 cells, a drug‐resistant CML cell line.…”