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Mir-506 Acts As a Tumor Suppressor by Directly Targeting the Hedgehog Pathway Transcription Factor Gli3 in Human Cervical Cancer

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Mir-506 Acts As a Tumor Suppressor by Directly Targeting the Hedgehog Pathway Transcription Factor Gli3 in Human Cervical Cancer Oncogene (2015) 34, 717–725 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer S-Y Wen1,2,3,8, Y Lin2,8, Y-Q Yu4, S-J Cao5, R Zhang6, X-M Yang3,JLi3, Y-L Zhang3, Y-H Wang3, M-Z Ma3, W-W Sun5, X-L Lou5, J-H Wang7, Y-C Teng1 and Z-G Zhang3 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. Oncogene (2015) 34, 717–725; doi:10.1038/onc.2014.9; published online 10 March 2014 INTRODUCTION diseases and malignant carcinomas. miR-506 expression has been Cervical carcinoma represents the third most common female shown to be upregulated in kidney allografts bearing interstitial cancer, with recently increasing incidence.1 The long-term (5-year) fibrosis and tubular atrophy and in primary biliary cirrhosis.10,11 survival of advanced cervical cancer patients only improved However, the expression pattern of miR-506 is complicated, even 3% by combined chemotherapy and radiotherapy, as compared contradictory, in different types of malignant carcinoma, indicat- with radiotherapy along.2 Therefore, it is urgent to uncover ing the complex role of miR-506 in cancer development. miR-506 the molecular mechanisms of cervical carcinoma and identify has been demonstrated to act as an oncogene in melanomas12 potential therapeutic targets to improve treatment. and can confer chemoresistance in colon cancer.13 In contrast, MicroRNAs (miRNAs) are non-coding RNA molecules of 20–24 miR-506 functions as a tumor suppressor in ovarian cancer14 and nucleotides that modulate the translational efficiency or stability suppresses malignant transformation in lung cancer.15 Using three of target messenger RNAs.3 Accumulating evidence has indicated different miRNA target prediction algorithms (PicTar, TargetScan that miRNAs are critical regulators of cancer progression that are and miRanda), we identified thousands of cancer-related genes involved in cancer cell proliferation, differentiation, apoptosis and that may be potential targets of miR-506. However, only two of – metastasis.4 8 miR-506 was identified by Bentwich et al.9 as a these genes, PPARα13 and SNAI2,14 have been shown to be direct component of an X chromosome-linked miRNA cluster in the targets of miR-506 by experimental analysis. primate testis. The genomic location of miR-506 is conserved in The zinc-finger protein Gli3, a mediator of Sonic hedge- mouse, dog, primate and ground squirrel. The biological function hog signaling, is also predicted to be a potential target of miR-506 has not been well studied. Currently, only a limited of miR-506. Several studies have shown that Gli3 has an number of reports exist regarding the roles of miR-506 in benign important role in cancer progression by stimulating cancer cell 1Department of Obstetrics & Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China; 2Department of Obstetrics & Gynecology, International Peace Maternity & Child Health Hospital of the China Welfare Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; 3State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; 4Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, PR China; 5Department of Obstetrics and Gynecology, Shanghai Songjiang District Central Hospital, Shanghai, PR China; 6Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, PR China and 7Department of Obstetrics and Gynecology, Southern Medical University, Guangzhou, PR China. Correspondence: Dr Y-C Teng, Department of Obstetrics & Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yisan Road, Shanghai 200233, PR China or Dr Z-G Zhang, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Room 428, Wenxuan Building of Medicine, 800 Dongchuan Road, Shanghai 200240, PR China. E-mail: [email protected] or [email protected] 8These authors contributed equally to this work. Received 27 June 2013; revised 2 February 2014; accepted 3 February 2014; published online 10 March 2014 miR-506 suppresses cervical cancer growth S-Y Wen et al 718 proliferation.16,17 In gynecological cancers, only one study proliferation. We selected two cervical cancer cell lines, Caski and has reported high expression of Gli3 in endometrial SiHa, to perform overexpression and/or knockdown experiments. adenocarcinoma.18 Although both miR-506 and Gli3 have been The proliferation rate of Caski cells stably transfected with implicated in cancer progression, the molecular mechanisms by sh-miR-506 was clearly increased compared with negative control which they affect cancer development, particularly cervical cells (Figure 2a). In contrast, the proliferation rate of SiHa cells carcinoma, remain unclear. transiently transfected with miR-506 mimics was significantly In this study, we found that miR-506 was downregulated in decreased compared with vector control cells (Figure 2b). To approximately 80% of our cervical cancer samples and was further evaluate the effect of miR-506 on cervical cancer cell inversely correlated with Ki-67, indicating that miR-506 expression proliferation in vivo, Caski cells stably expressing sh-miR-506 or may be related with cervical cell proliferation. Gain-of-function negative control cells were subcutaneously injected into nude and loss-of-function studies demonstrated that miR-506 acts as a mice. The mice were killed 4 weeks later, and the weights of the tumor suppressor by affecting cervical cancer growth, apoptosis resulting tumors were measured. The tumor weights in the and chemosensitivity. Furthermore, the hedgehog pathway miR-506-silenced group were significantly higher than those in the transcription factor Gli3 was identified as a direct functional negative control group (Figures 2c and d). These results indicate target of miR-506 in cervical cancer. that miR-506 suppresses cervical cancer cell proliferation both in vitro and in vivo. RESULTS miR-506 expression is downregulated and inversely correlates miR-506 induces cell cycle arrest of cervical cancer cells at with Ki-67 expression in human cervical cancer the G1/S transition fi To evaluate the expression and significance of miR-506 in cervical As miR-506 signi cantly suppressed cervical cancer cell prolifera- cancer, we first evaluated miR-506 expression in 50 matched pairs tion, we next aimed to determine whether miR-506 affects cell of cervical cancer and corresponding non-tumorous cervical cycle progression of cervical cancer cells. Cell cycle distribution tissues using real-time quantitative reverse transcriptase–PCR with analysis of Caski cells treated with nocodazole showed that fi normalization against an endogenous control (U6 RNA). miR-506 silencing of miR-506 resulted in a signi cant decrease in the expression was clearly downregulated in cervical cancer tissues cellular population in G0/G1 phase but a sharp increase in S phase compared with non-tumorous cervical tissues (Figures 1a and b). (Figure 3a). Consistent with this result, miR-506 mimics noticably miR-506 expression was inversely correlated with Ki-67 in these induced G1 phase arrest of both Caski and SiHa cells treated with clinical samples (Figure 1c), suggesting that miR-506 may have a nocodazole (Figures 3b and c). critical role in regulating cell proliferation. However, the specific function of miR-506 in human cervical cancer remained elusive. miR-506 induced apoptosis and enhanced chemosensitivity of cervical cancer cells miR-506 inhibits cervical cancer cell proliferation and xenograft We
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