title: The upregulation of signal transducer and activator of transcription 5-dependent microRNA-182 and microRNA-96 promotes ovarian cancer cell proliferation by targeting forkhead box O3 upon leptin stimulation.
abstract: Leptin overexpression contributes to the tumorigenesis of ovarian cancer. However, the functional mechanism and effects remain unclear. The aberrant expression of tumor-related microRNAs may play an important role in the development of cancer. In this report, we demonstrate that crosstalk between leptin and microRNA-182 and microRNA-96 affects the transformation and proliferation of ovarian cancer cells. Our results showed that leptin enhanced the colony formation of ovarian cancer cells in soft agar. A water-soluble tetrazolium salts assay revealed that leptin promoted ovarian cancer cell (SKOV3 and A2780 cells) proliferation in a time- and dose-dependent manner. The growth effects of leptin on ovarian cancer cells were mediated via the reduced expression of forkhead box O3 and its downstream targets p27 and Bim. We demonstrated that leptin upregulated miRNAs that target forkhead box O3 via luciferase reporter assay. Further examination indicated that only the inhibition of microRNA-182 and/or microRNA-96 rescued the expression of forkhead box O3 inhibited by leptin, and their mimics promoted the proliferation of ovarian cancer cells. Moreover, the signal transducer and activator of transcription 5 pathway, but not the signal transducer and activator of transcription 3 pathway, was implicated in the leptin-mediated expression of microRNA-182 and microRNA-96. In conclusion, our findings suggest that the upregulation of microRNA-182 and microRNA-96 targeting forkhead box O3 plays a significant role in the pro-proliferation effect of leptin on ovarian cancer cells, which might provide preliminary experimental clues for the development of new therapies against ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Xu
authors.forename: Zhaogang
authors.initials: Z
authors.lastname: Dong
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Li
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Yang
authors.forename: Zeng
authors.initials: Z
authors.lastname: Yuan
authors.forename: Xun
authors.initials: X
authors.lastname: Qu
authors.forename: Beihua
authors.initials: B
authors.lastname: Kong
mesh_terms: D049109:Cell Proliferation; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D020738:Leptin; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D050799:STAT5 Transcription Factor