title: MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway.
abstract: 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.
authors.affiliation: Shanghai Tenth People's Hospital, Medical School, Tongji University, Shanghai, 200072, China, liutelt@163.com.
authors.forename: Te
authors.initials: T
authors.lastname: Liu
authors.forename: Wenxing
authors.initials: W
authors.lastname: Qin
authors.forename: Lengchen
authors.initials: L
authors.lastname: Hou
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases