Abstract
Karyopherin alpha 2 (KPNA2) is a nuclear transport protein upregulated in many cancers. Our previous study has identified KPNA2 overexpression in epithelial ovarian carcinoma (EOC) tissues, which predicts poor prognosis. However, the mechanism of KPNA2 overexpression in EOC remains unclear. This study aimed to examine the role of miRNA in KPNA2 dysregulation. Our results showed that miR-26b was downregulated in EOC samples, and correlated inversely with KPNA2 expression. Low expression of miR-26b was associated with advanced FIGO stage, poor differentiation, higher risk of distant metastasis and recurrence. Downregulation of miR-26b predicted poor disease-free survival and overall survival in EOC patients. KPNA2 was validated as a direct target of miR-26b. Knockdown of KPNA2 or ectopic expression of miR-26b could downregulate OCT4, vimentin and upregulate E-cadherin. Reintroduction of KPNA2 partially abrogated the suppression effect induced by miR-26b. We further verified that miR-26b/KPNA2/OCT4 axis inhibited EOC cell viability, migratory ability and sphere-forming capacity in vitro and in vivo. In conclusion, our results reveal that miR-26b is downregulated in EOC, and directly targets KPNA2. miR-26b/KPNA2 axis suppresses tumor proliferation and metastasis through decreasing OCT4 expression, which is indicative of the important role of miR-26b/KPNA2/OCT4 axis in EOC carcinogenesis and progression.
Highlights
Epithelial ovarian carcinoma (EOC) is the most common histological type of ovarian cancer, representing the most fatal gynecological malignancy among women worldwide
The biological functions of Karyopherin alpha 2 (KPNA2) have been examined in some cancer cell lines; for example, overexpression of KPNA2 in a benign breast cell line could increase cell colony formation ability and migration activity in a manner similar to that in malignant cells [18]
Cell migratory ability and viability can be enhanced by KPNA2 in lung cancer cell lines [13]
Summary
Epithelial ovarian carcinoma (EOC) is the most common histological type of ovarian cancer, representing the most fatal gynecological malignancy among women worldwide. It was estimated that 21,980 new cases and 14,270 deaths occured in 2014 as a consequence of EOC [1]. Understanding the molecular pathogenesis and uncovering molecular biomarkers of EOC would facilitate early detection and improve the survival of ovarian cancer patients. By using cDNA microarrays, we previously found that karyopherin α2 (KPNA2) was overexpressed in EOC tissues compared to paired normal human ovarian surface epithelial (HOSE) tissues. Subsequent studies have shown that the overexpression of KPNA2 was correlated with a www.impactjournals.com/oncotarget poor prognosis in EOC [2] and ovarian malignant germ cell tumors [3]. We observed that KPNA2 could promote cell proliferation and tumorigenicity by enhancing c-Myc expression and reducing FOXO3a expression in EOC, suggesting that KPNA2 might be a potential therapeutic target in EOC [4]
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