Abstract
miRNAs have emerged as a pivotal component of gene regulatory networks, mediating cytokines secretion, cell cycle, and differentiation regulation. However, how miRNAs collaborate with transcription factors and downstream effector proteins that determine the fate of ovarian cancer cells remains to be understood, especially regarding to mechanism of tumor angiogenesis regulation. Based on the qRT-PCR and IHC analysis, we found that miR-6086 was maintained a very low level both in ovarian cancer cell lines and tissues. Further, we identified OC2 and EGFL6 as the direct targets of miR-6086 by luciferase assay and we observed an inverse relationship between the expression of miR-6086 and the OC2/VEGFA/EGFL6 axis. The Western blotting analysis suggested that OC2 could directly upregulate VEGFA and indirectly up-regulate EGFL6 through VEGFA. Moreover, miR-6086 could indirectly downregulate VEGFA through OC2. In addition, miR-6086, siOC2 and siEGFL6 could negatively regulate the tumor growth and angiogenesis of ovarian cancer (Skov3) in the animal studies, with the inhibition rates of 77.07%, 69.89%, and 73.62%, respectively (**p < 0.01). Moreover, the tumor cell proliferation, migration, and invasion of ovarian cancer cell lines (Caov3 and Skov3) and vascular formation (HUVECs) were significantly suppressed in vitro, by decreasing the AKT/MAPK pathways (*p < 0.05). Taken together, our results reveal that miR-6086 can suppress the angiogenesis networks in ovarian cancer by down-regulating the OC2/VEGFA/EGFL6 axis, directly or indirectly, which may provide potential targets for tumor therapeutics.
Highlights
Ovarian cancer is one of the leading causes of death among female genital malignancies with high mortality, high recurrence rate, and low survival outcome[1]
Angiogenesis is an essential program for ovarian cancer, which is induced by numerous angiogenic factors, such as vascular endothelial growth factor A (VEGFA), fibroblast growth factor (FGF2), platelet-derived growth factor subunit A (PDGFA), EGF
Our analysis identified that OC2 and EGFL6 were the direct targets of miR-6086 and we further demonstrated the relationship between miR-6086 and the OC2/VEGFA/EGFL6 axis in ovarian cancer
Summary
Ovarian cancer is one of the leading causes of death among female genital malignancies with high mortality, high recurrence rate, and low survival outcome[1] Therapy of this malignant tumor suffers from lack of effective strategies, clinical heterogeneity, and poor prognosis in patients[2]. MicroRNAs (miRNAs) have been shown to play key roles in angiogenesis and their deregulation has a global impact on tumor angiogenesis networks, offering newer opportunities for cancer therapy[10]. These are endogenous small noncoding RNAs that act as post-transcriptional regulators of gene expression by binding the 3′untranslated region (3′UTR) of target transcripts, leading to translational repression or degradation of mRNA11–13. The action mode of miR-6086 in tumor angiogenesis remains to be fully understood and any unknown mechanisms of vessel formation and regulation networks need further exploration
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