MiR-26b/KPNA2 axis inhibits epithelial ovarian carcinoma proliferation and metastasis through downregulating OCT4

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.

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

“…Overexpression of KPNA2 in EOC correlates with poor prognosis (94). An inverse correlation between KPNA2 and miR-26a expression in EOC has been observed (90). The miR26/KPNA2/OCT4 axis inhibits EOC proliferation, migration and sphere-forming ability in vitro and in vivo (90).…”

“…miR-26 is down-regulated in EOC and low expression is associated with FIGO stage, poor disease free survival, higher risk of distant metastases, recurrence and overall survival (90). Karyopherin α2 (KPNA2) was identified as one of its targets (90).…”

“…miR-26 is down-regulated in EOC and low expression is associated with FIGO stage, poor disease free survival, higher risk of distant metastases, recurrence and overall survival (90). Karyopherin α2 (KPNA2) was identified as one of its targets (90). KPNA2 is a nuclear transport protein (91) and its down-regulation promotes expression of stem cell pluripotency homeobox transcription factor 4 (OCT4) (90,92,93).…”

“…Karyopherin α2 (KPNA2) was identified as one of its targets (90). KPNA2 is a nuclear transport protein (91) and its down-regulation promotes expression of stem cell pluripotency homeobox transcription factor 4 (OCT4) (90,92,93). Overexpression of KPNA2 in EOC correlates with poor prognosis (94).…”

“…An inverse correlation between KPNA2 and miR-26a expression in EOC has been observed (90). The miR26/KPNA2/OCT4 axis inhibits EOC proliferation, migration and sphere-forming ability in vitro and in vivo (90). Ectopic expression of miR-26b down-regulates OCT4 and vimentin levels and up-regulates E-cadherin expression (90).…”