MicroRNA-218 Inhibits Cell Cycle Progression and Promotes Apoptosis in Colon Cancer by Downregulating BMI1 Polycomb Ring Finger Oncogene

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2012 Dec 21

PMID 23255074

Citations 78

Authors

Xinqi He

Yujuan Dong

Chung Wah Wu

Zengren Zhao

Simon S M Ng

Francis K L Chan

Joseph J Y Sung

Jun Yu

Affiliations

Soon will be listed here.

Abstract

Deregulated miRNAs participate in colorectal carcinogenesis. In this study, miR-218 was found to be downregulated in human colorectal cancer (CRC) by miRNA profile assay. miR-218 was silenced or downregulated in all five colon cancer cells (Caco2, HT29, SW620, HCT116 and LoVo) relative to normal colon tissues. miR-218 expression was significantly lower in 46 CRC tumor tissues compared with their adjacent normal tissues (P < 0.001). Potential target genes of miR-218 were predicted and BMI1 polycomb ring finger oncogene (BMI-1), a polycomb ring finger oncogene, was identified as one of the potential targets. Upregulation of BMI-1 was detected in CRC tumors compared with adjacent normal tissues (P < 0.001) and in all five colon cancer cell lines. Transfection of miR-218 in colon cancer cell lines (HCT116, HT29) significantly reduced luciferase activity of the wild-type construct of BMI-1 3' untranslated region (3'UTR) (P < 0.001), whereas this effect was not seen in the construct with mutant BMI-1 3'UTR, indicating a direct and specific interaction of miR-218 with BMI-1. Ectopic expression of miR-218 in HCT116 and HT29 cells suppressed BMI-1 mRNA and protein expression. In addition, miR-218 suppressed protein expression of BMI-1 downstream targets of cyclin-dependent kinase 4, a cell cycle regulator, while upregulating protein expression of p53. We further revealed that miR-218 induced apoptosis (P < 0.01), inhibited cell proliferation (P < 0.05) and promoted cell cycle arrest in the G2 phase (P < 0.01). In conclusion, miR-218 plays a pivotal role in CRC development through inhibiting cell proliferation and cycle progression and promoting apoptosis by downregulating BMI-1.

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References

Tateishi K, Ohta M, Kanai F, Guleng B, Tanaka Y, Asaoka Y . Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin Cancer Res. 2006; 12(23):6960-6. DOI: 10.1158/1078-0432.CCR-06-0449. View

Galasso M, Sandhu S, Volinia S . MicroRNA expression signatures in solid malignancies. Cancer J. 2012; 18(3):238-43. DOI: 10.1097/PPO.0b013e318258b5f4. View

Gao C, Zhang Z, Liu W, Xiao S, Gu W, Lu H . Reduced microRNA-218 expression is associated with high nuclear factor kappa B activation in gastric cancer. Cancer. 2009; 116(1):41-9. DOI: 10.1002/cncr.24743. View

Douglas D, Hao-Ru Hsu J, Hung L, Cooper A, Abdueva D, van Doorninck J . BMI-1 promotes ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res. 2008; 68(16):6507-15. PMC: 2570201. DOI: 10.1158/0008-5472.CAN-07-6152. View

Shivapurkar N, Maitra A, Milchgrub S, Gazdar A . Deletions of chromosome 4 occur early during the pathogenesis of colorectal carcinoma. Hum Pathol. 2001; 32(2):169-77. DOI: 10.1053/hupa.2001.21560. View

Sakamuro D, Eviner V, Elliott K, Showe L, White E, Prendergast G . c-Myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanisms. Oncogene. 1995; 11(11):2411-8. View

Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90. DOI: 10.3322/caac.20107. View

Burgess A, Wigan M, Giles N, DePinto W, Gillespie P, Stevens F . Inhibition of S/G2 phase CDK4 reduces mitotic fidelity. J Biol Chem. 2006; 281(15):9987-95. DOI: 10.1074/jbc.M512714200. View

Gabrielli B, Sarcevic B, Sinnamon J, Walker G, Castellano M, Wang X . A cyclin D-Cdk4 activity required for G2 phase cell cycle progression is inhibited in ultraviolet radiation-induced G2 phase delay. J Biol Chem. 1999; 274(20):13961-9. DOI: 10.1074/jbc.274.20.13961. View

10.

Davidson M, Larsen J, Yang I, Hayward N, Clarke B, Duhig E . MicroRNA-218 is deleted and downregulated in lung squamous cell carcinoma. PLoS One. 2010; 5(9):e12560. PMC: 2933228. DOI: 10.1371/journal.pone.0012560. View

11.

Tatarano S, Chiyomaru T, Kawakami K, Enokida H, Yoshino H, Hidaka H . miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer. Int J Oncol. 2011; 39(1):13-21. DOI: 10.3892/ijo.2011.1012. View

12.

Sorrentino B . Clinical strategies for expansion of haematopoietic stem cells. Nat Rev Immunol. 2004; 4(11):878-88. DOI: 10.1038/nri1487. View

13.

Schetter A, Harris C . Alterations of microRNAs contribute to colon carcinogenesis. Semin Oncol. 2011; 38(6):734-42. PMC: 3217180. DOI: 10.1053/j.seminoncol.2011.08.009. View

14.

Dallol A, Morton D, Maher E, Latif F . SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells. Cancer Res. 2003; 63(5):1054-8. View

15.

Li D, Tang H, Fan J, Yan D, Zhou C, Li S . Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer. J Cancer Res Clin Oncol. 2009; 136(7):997-1006. DOI: 10.1007/s00432-009-0745-7. View

16.

Kang M, Kim R, Kim S, Yip F, Shin K, Dimri G . Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival. Br J Cancer. 2006; 96(1):126-33. PMC: 2360223. DOI: 10.1038/sj.bjc.6603529. View

17.

Wu J, Hu D, Yang G, Zhou J, Yang C, Gao Y . Down-regulation of BMI-1 cooperates with artemisinin on growth inhibition of nasopharyngeal carcinoma cells. J Cell Biochem. 2011; 112(7):1938-48. DOI: 10.1002/jcb.23114. View

18.

Vogelstein B, Kinzler K . Cancer genes and the pathways they control. Nat Med. 2004; 10(8):789-99. DOI: 10.1038/nm1087. View

19.

Li Q, Zhu F, Chen P . miR-7 and miR-218 epigenetically control tumor suppressor genes RASSF1A and Claudin-6 by targeting HoxB3 in breast cancer. Biochem Biophys Res Commun. 2012; 424(1):28-33. DOI: 10.1016/j.bbrc.2012.06.028. View

20.

Alajez N, Lenarduzzi M, Ito E, Hui A, Shi W, Bruce J . MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer Res. 2011; 71(6):2381-91. DOI: 10.1158/0008-5472.CAN-10-2754. View