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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

MiR-216b inhibits cell proliferation by targeting FOXM1 in cervical cancer cells and is associated with better prognosis

Authors: Shanyang He, Bing Liao, Yalan Deng, Chang Su, Jiuling Tuo, Jun Liu, Shuzhong Yao, Lin Xu

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Our previous study showed FOXM1 expression was significantly up-regulated in cervical cancer, and was associated with poor prognosis. To clarify miRNAs-FOXM1 modulation pathways, in this study, we investigated the relationships between miR-216b and FOXM1 and the role of miR-216b in cell proliferation and prognosis of cervical cancer patients.

Methods

Western blotting and qPCR were used to determine expression of FOXM1, cell cycle related factors and miR-216b level. MiR-216b overexpression and inhibited cell models were constructed, and siRNA was used for FOXM1 silencing. Cell proliferation was analyzed by MTT and colony formation assay. Dual luciferase reporter assay system was used to clarify the relationships between miR-216b and FOXM1. Kaplan-Meier survival analysis was used to evaluate prognosis.

Results

MiR-216b was down-regulated in cervical cancer cells and tissues, and its ectopic expression could decrease cell proliferation. Western blotting analysis showed miR-216b can inhibit cell proliferation by regulating FOXM1-related cell cycle factors, suppressing cyclinD1, c-myc, LEF1 and p-Rb and enhancing p21 expression. Repressing of miR-216b stimulated cervical cancer cell proliferation, whereas silencing FOXM1 expression could reverse this effect. Western blotting and luciferase assay results proved FOXM1 is a direct target of miR-216b. Survival analysis showed higher level of miR-216b was associated with better prognosis in cervical cancer patients.

Conclusions

FOXM1 expression could be suppressed by miR-216b via direct binding to FOXM1 3′-UTR and miR-216b could inhibit cell proliferation by regulating FOXM1 related Wnt/β-catenin signal pathway. MiR-216b level is related to prognosis in cervical cancer patients and may serve as a potential prognostic marker.
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Literature
1.
2.
Leyden WA, Manos MM, Geiger AM, Weinmann S, Mouchawar J, Bischoff K, Yood MU, Gilbert J, Taplin SH. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97(9):675–83. PubMed: 15870438 CrossRefPubMed
3.
He SY, Shen HW, Xu L, Zhao XH, Yuan L, Niu G, You ZS, Yao SZ. FOXM1 promotes tumor cell invasion and correlates with poor prognosis in early-stage cervical cancer. Gynecol Oncol. 2012;127(3):601–10. PubMed: 22943878 CrossRefPubMed
4.
5.
Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7. PubMed: 17401365 CrossRefPubMed
6.
Nyholm AM, Lerche CM, Manfé V, Biskup E, Johansen P, Morling N, Thomsen BM, Glud M, Gniadecki R. miR-125b induces cellular senescence in malignant melanoma. BMC Dermatol. 2014;14:8. PubMed: 24762088 CrossRefPubMedPubMedCentral
7.
Presneau N, Eskandarpour M, Shemais T, Henderson S, Halai D, Tirabosco R, Flanagan AM. MicroRNA profiling of peripheral nerve sheath tumours identifies miR-29c as a tumour suppressor gene involved in tumour progression. Br J Cancer. 2013;108(4):964–72. PubMed: 23175151 CrossRefPubMed
8.
Luedde T. MicroRNA-151 and its hosting gene FAK (focal adhesion kinase) regulate tumor cell migration and spreading of hepatocellular carcinoma. Hepatology. 2010;52(3):1164–6. PubMed: 20812359 CrossRefPubMed
9.
10.
11.
Huang X, Qin J, Lu S. Up-regulation of miR-877 induced by paclitaxel inhibits hepatocellular carcinoma cell proliferation though targeting FOXM1. Int J Clin Exp Pathol. 2015;8(2):1515–24. PubMed: 25973036 PubMedPubMedCentral
12.
13.
Li Z, Ying X, Chen H, Ye P, Shen Y, Pan W, Zhang L. MicroRNA-194 inhibits the epithelial-mesenchymal transition in gastric cancer cells by targeting FoxM1. Dig Dis Sci. 2014;59(9):2145–52. PubMed: 24748184 CrossRefPubMed
14.
Xu K, Liu X, Mao X, Xue L, Wang R, Chen L, Chu X. MicroRNA-149 suppresses colorectal cancer cell migration and invasion by directly targeting forkhead box transcription factor FOXM1. Cell Physiol Biochem. 2015;35(2):499–515. PubMed: 25613903 CrossRefPubMed
15.
Inoguchi S, Seki N, Chiyomaru T, Ishihara T, Matsushita R, Mataki H, Itesako T, Tatarano S, Yoshino H, Goto Y, Nishikawa R, Nakagawa M, Enokida H. Tumour-suppressive microRNA-24-1 inhibits cancer cell proliferation through targeting FOXM1 in bladder cancer. FEBS Lett. 2014;588(17):3170–9. PubMed: 24999187 CrossRefPubMed
16.
Yungang W, Xiaoyu L, Pang T, Wenming L, Pan X. miR-370 targeted FoxM1 functions as a tumor suppressor in laryngeal squamous cell carcinoma (LSCC). Biomed Pharmacother. 2014;68(2):149–54. PubMed: 24055400 CrossRefPubMed
17.
18.
Li J, Wang Y, Luo J, Fu Z, Ying J, Yu Y, Yu W. miR-134 inhibits epithelial to mesenchymal transition by targeting FOXM1 in non-small cell lung cancer cells. FEBS Lett. 2012;586(20):3761–5. PubMed: 23010597 CrossRefPubMed
19.
Zhang X, Zeng J, Zhou M, Li B, Zhang Y, Huang T, Wang L, Jia J, Chen C. The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia. Mol Cancer. 2012;11:56. PubMed: 22900969 CrossRefPubMedPubMedCentral
20.
Garg M, Kanojia D, Saini S, Suri S, Gupta A, Surolia A, Suri A. Germ cell-specific heat shock protein 70-2 is expressed in cervical carcinoma and is involved in the growth, migration, and invasion of cervical cells. Cancer. 2010;116(16):3785–96. PubMed: 20564126 CrossRefPubMed
21.
Deng M, Tang H, Zhou Y, Zhou M, Xiong W, Zheng Y, Ye Q, Zeng X, Liao Q, Guo X, Li X, Ma J, Li G. miR-216b suppresses tumor growth and invasion by targeting KRAS in nasopharyngeal carcinoma. J Cell Sci. 2011;124(Pt 17):2997–3005. PubMed: 21878506 CrossRefPubMed
22.
Edward DP, Alkatan H, Rafiq Q, Eberhart C, Al Mesfer S, Ghazi N, Al Safieh L, Kondkar AA, Abu Amero KK. MicroRNA profiling in intraocular medulloepitheliomas. PLoS One. 2015;10(3):e0121706. PubMed: 25807141 CrossRefPubMedPubMedCentral
23.
Li XR, Chu HJ, Lv T, Wang L, Kong SF, Dai SZ. miR-342-3p suppresses proliferation, migration and invasion by targeting FOXM1 in human cervical cancer. FEBS Lett. 2014;588(17):3298–307. PubMed: 25066298 CrossRefPubMed
24.
Fu HJ, Zhu J, Yang M, Zhang ZY, Tie Y, Jiang H, Sun ZX, Zheng XF. A novel method to monitor the expression of microRNAs. Mol Biotechnol. 2006;32(3):197–204. PubMed: 16632886 CrossRefPubMed
25.
Chen D, Huang J, Zhang K, Pan B, Chen J, De W, Wang R, Chen L. MicroRNA-451 induces epithelial-mesenchymal transition in docetaxel-resistant lung adenocarcinoma cells by targeting proto-oncogene c-Myc. Eur J Cancer. 2014;50(17):3050–67. PubMed: 25310895 CrossRefPubMed
26.
Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Tan Y, Ackerson T, Costa RH. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol. 2005;25(24):10875–94. PubMed: 16314512 CrossRefPubMedPubMedCentral
27.
Wierstra I, Alves J. Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol Chem. 2006;387(7):949–62. PubMed: 16913845 PubMed
28.
Wierstra I, Alves J. Cyclin E/Cdk2, P/CAF, and EIA regulate the transactivation of the c-myc promoter by FOXM1. Biochem Biophys Res Commun. 2008;368(1):107–15. PubMed: 18206647 CrossRefPubMed
29.
Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, Huang H, Xue J, Liu M, Wang Y, Sawaya R, Xie K, Yung WK, Medema RH, He X, Huang S. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20(4):427–42. PubMed: 22014570 CrossRefPubMedPubMedCentral
30.
Laoukili J, Kooistra MR, Bras A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH. FOXM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol. 2005;7(2):126–36. PubMed: 15654331 CrossRefPubMed
31.
Laoukili J, Stahl M, Medema RH. FOXM1: at the crossroads of ageing and cancer. Biochim Biophys Acta. 2007;1775(1):92–102. PubMed: 17014965 PubMed
32.
Li Q, Zhang N, Jia Z, Le X, Dai B, Wei D, Huang S, Tan D, Xie K. Critical role and regulation of transcription factor FOXM1 in human gastric cancer angiogenesis and progression. Cancer Res. 2009;69(8):3501–9. PubMed: 19351851 CrossRefPubMedPubMedCentral
33.
Yang DK, Son CH, Lee SK, Choi PJ, Lee KE, Roh MS. Forkhead box M1 expression in pulmonary squamous cell carcinoma: correlation with clinicopathologic features and its prognostic significance. Hum Pathol. 2009;40(4):464–70. PubMed: 19121844 CrossRefPubMed
34.
Li Y, Ligr M, McCarron JP, Daniels G, Zhang D, Zhao X, Ye F, Wang J, Liu X, Osman I, Mencher SK, Lepor H, Wang LG, Ferrari A, Lee P. Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion. Clin Cancer Res. 2011;17(13):4414–24. PubMed: 21606178 CrossRefPubMedPubMedCentral
35.
Wang Y, Xu P, Yao J, Yang R, Shi Z, Zhu X, Feng X, Gao S. MicroRNA-216b is Down-Regulated in Human Gastric Adenocarcinoma and Inhibits Proliferation and Cell Cycle Progression by Targeting Oncogene HDAC8. Target Oncol. 2016;11(2):197–207. PubMed: 26408293 CrossRefPubMed
36.
Zheng L, Zhang X, Yang F, Zhu J, Zhou P, Yu F, Hou L, Xiao L, He Q, Wang B. Regulation of the P2X7R by microRNA-216b in human breast cancer. Biochem Biophys Res Commun. 2014;452(1):197–204. PubMed: 25078617 CrossRefPubMed
37.
Kim SY, Lee YH, Bae YS. MiR-186, miR-216b, miR-337-3p, and miR-760 cooperatively induce cellular senescence by targeting α subunit of protein kinase CKII in human colorectal cancer cells. Biochem Biophys Res Commun. 2012;429(3–4):173–9. PubMed: 23137536 CrossRefPubMed
38.
Zheng WW, Zhou J, Zhang CH, Liu XS. MicroRNA-216b is downregulated in hepatocellular carcinoma and inhibits HepG2 cell growth by targeting Forkhead box protein M1. Eur Rev Med Pharmacol Sci. 2016;20(12):2541–50. PubMed: 27383303 PubMed
39.
Sun M, Wang X, Tu C, Wang SQJ, Xiao S. microRNA-216b inhibits cell proliferation and migration in human melanoma by targeting FOXM1 in vitro and in vivo. Cell Biol Int. 2017; doi:10.​1002/​cbin.​10754. PubMed: 28225180
40.
Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–84. PubMed: 28112728CrossRef
Metadata
Title
MiR-216b inhibits cell proliferation by targeting FOXM1 in cervical cancer cells and is associated with better prognosis
Authors
Shanyang He
Bing Liao
Yalan Deng
Chang Su
Jiuling Tuo
Jun Liu
Shuzhong Yao
Lin Xu
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3650-5

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