title: Metformin inhibits epithelial-mesenchymal transition in prostate cancer cells: involvement of the tumor suppressor miR30a and its target gene SOX4.
abstract: Tumor metastasis is the leading cause of mortality and morbidity of prostate cancer (PCa) patients. Epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. Recent evidence suggested that diabetic patients treated with metformin have lower PCa risk and better prognosis. This study was aimed to investigate the effects of metformin on EMT in PCa cells and the possible microRNA (miRNA)-based mechanisms. MiRNAs have been shown to regulate various processes of cancer metastasis. We herein showed that metformin significantly inhibits proliferation of Vcap and PC-3 cells, induces G0/G1 cell cycle arrest and inhibits invasiveness and motility capacity of Vcap cells. Metformin could inhibit TGF-β-induced EMT in Vcap cells, as manifested by inhibition of the increase of N-cadherin (p=0.013), Vimentin (p=0.002) and the decrease of E-cadherin (p=0.0023) and β-catenin (p=0.034) at mRNA and protein levels. Notably, we demonstrated significant upregulation of miR30a levels by metformin (P<0.05) and further experiments indicated that miR30a significantly inhibits proliferation and EMT process of Vcap cells. Interestingly, we identified that SOX4, a previously reported oncogenic transcriptional factor and modulator of EMT, is a direct target gene of miR30a. Finally, we screened the expression of miR30a and SOX4 in 84 PCa cases with radical prostatectomy. Of note, SOX4 overexpression is significantly associated with decreased levels of miR30a in PCa cases. In all, our study suggested that inhibition of EMT by metformin in PCa cells may involve upregulation of miR30a and downregulation of SOX4.
authors.affiliation: Department of Pharmacy, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
authors.forename: Chengwu
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan 250012, China; Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences, Jinan 250012, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, The Fourth People's Hospital of Jinan, Jinan 250031, China.
authors.forename: Quanping
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: Pingtian
authors.initials: P
authors.lastname: Xia
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: Muyi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan 250012, China; Department of Pathology, Qilu Hospital, Shandong University, Jinan 250012, China. Electronic address: boh@sdu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Han
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055751:SOXC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D007004:Hypoglycemic Agents; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D008687:Metformin; D008156:Luciferases
keywords: Epithelial–mesenchymal transition; Metformin; Prostate cancer; SOX4; miR30a