title: miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer.
abstract: Although significant advances have recently been made in the diagnosis and treatment of cervical carcinoma, the long-term survival rate for advanced cervical cancer remains low. Therefore, an urgent need exists to both uncover the molecular mechanisms and identify potential therapeutic targets for the treatment of cervical cancer. MicroRNAs (miRNAs) have important roles in cancer progression and could be used as either potential therapeutic agents or targets. miR-506 is a component of an X chromosome-linked miRNA cluster. The biological functions of miR-506 have not been well established. In this study, we found that miR-506 expression was downregulated in approximately 80% of the cervical cancer samples examined and inversely correlated with the expression of Ki-67, a marker of cell proliferation. Gain-of-function and loss-of-function studies in human cervical cancer, Caski and SiHa cells, demonstrated that miR-506 acts as a tumor suppressor by inhibiting cervical cancer growth in vitro and in vivo. Further studies showed that miR-506 induced cell cycle arrest at the G1/S transition, and enhanced apoptosis and chemosensitivity of cervical cancer cell. We subsequently identified Gli3, a hedgehog pathway transcription factor, as a direct target of miR-506 in cervical cancer. Furthermore, Gli3 silencing recapitulated the effects of miR-506, and reintroduction of Gli3 abrogated miR-506-induced cell growth arrest and apoptosis. Taken together, we conclude that miR-506 exerts its anti-proliferative function by directly targeting Gli3. This newly identified miR-506/Gli3 axis provides further insight into the pathogenesis of cervical cancer and indicates a potential novel therapeutic agent for the treatment of cervical cancer.
authors.affiliation: 1] Department of Obstetrics & Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China [2] Department of Obstetrics & Gynecology, International Peace Maternity & Child Health Hospital of the China Welfare Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China [3] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Wen
authors.affiliation: Department of Obstetrics & Gynecology, International Peace Maternity & Child Health Hospital of the China Welfare Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, PR China.
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Songjiang District Central Hospital, Shanghai, PR China.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Cao
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, PR China.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: X-M
authors.initials: XM
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: M-Z
authors.initials: MZ
authors.lastname: Ma
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Songjiang District Central Hospital, Shanghai, PR China.
authors.forename: W-W
authors.initials: WW
authors.lastname: Sun
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Songjiang District Central Hospital, Shanghai, PR China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Lou
authors.affiliation: Department of Obstetrics and Gynecology, Southern Medical University, Guangzhou, PR China.
authors.forename: J-H
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Obstetrics & Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Teng
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Z-G
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; D019394:Ki-67 Antigen; D051741:Kruppel-Like Transcription Factors; C561508:MIRN506 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3