MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway
- 496 Downloads
The mechanism underlying the development of human ovarian cancer is poorly understood. The liver kinase protein, LKB1, is hypothesized to play a pivotal role in tumor cell proliferation and invasion capacity through regulation of p53 and p21/WAF1 expression. Previous studies suggest LKB1 may, in turn, be regulated by microRNA-17. Here, we examined the role of miR-17 in the expression of LKB1 and the downstream effects on proliferation and invasion capacity of normal ovarian cancer cells (OCCs) and ovarian stem cells. In this study, both the mRNA and protein expression levels of LKB1, p53, and p21 decreased in OCCs following transfection with a miR-17 expression plasmid. MiR-17 expression affected cell cycle regulation and stimulated the proliferation and invasion capacity of OCCs in vitro. ChIP assays indicated that the binding efficiency of p53 to the p21/WAF1 gene promoter was much lower in miR-17 transfected OCCs than in OCCs transfected with a mutated miR-17. Co-immunoprecipitation and western blotting showed significantly lower levels of p53 and p53 Ser15-pho in the miR-17 transfected OCCs as compared to the mutant miR-17 transfected OCCs. Xenograft experiments confirmed that suppression of tumor growth in vivo occurred in the absence of functional miR-17. These findings suggest that mature miR-17 expression may have an important role in the pathogenesis of human ovarian tumors through its interference with the LKB1-p53-p21/WAF1 pathway expression by epigenetic modification. These findings are of potential importance in the identification of novel therapeutic targets in human ovarian cancer.
KeywordsOvarian cancer Cancer stem cells LKB1-p53-p21/WAF1 pathway MicroRNA-17 Proliferation Tumorigenicity
This work was supported by a grant from the National Natural Science Foundation of China (No. 81202811) and project funded by the China Postdoctoral Science Foundation (No. 2014 M550250) and Shanghai Municipal Health Bureau Fund (No. 20124320) to Te Liu.
Conflicts of interest
- 28.Liu T, Chen Q, Huang Y, Huang Q, Jiang L, Guo L. Low microRNA-199a expression in human amniotic epithelial cell feeder layers maintains human-induced pluripotent stem cell pluripotency via increased leukemia inhibitory factor expression. Acta Biochim Biophys Sin (Shanghai). 2012;44:197–206.CrossRefGoogle Scholar
- 32.Rubatt JM, Darcy KM, Tian C, Muggia F, Dhir R, Armstrong DK, et al. Pre-treatment tumor expression of ERCC1 in women with advanced stage epithelial ovarian cancer is not predictive of clinical outcomes: a Gynecologic Oncology Group study. Gynecol Oncol. 2012;125:421–6.CrossRefPubMedPubMedCentralGoogle Scholar