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Molecular Medicine

, Volume 18, Issue 12, pp 1491–1498 | Cite as

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

  • Xinqi He
  • Yujuan Dong
  • Chung Wah Wu
  • Zengren Zhao
  • Simon S M Ng
  • Francis K L Chan
  • Joseph J Y Sung
  • Jun Yu
Research Article

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.

Notes

Acknowledgments

This project was supported by a National High-Tech R&D Program in China (863 Program, 2012AA02A506), National Natural Science Foundation of China (81072034) and an ITF fund in Hong Kong (project code ITS/276/11).

Supplementary material

10020_2012_18121491_MOESM1_ESM.pdf (343 kb)
MicroRNA-218 Inhibits Cell Cycle Progression and Promotes Apoptosis in Colon Cancer by Downregulating BMI1 Polycomb Ring Finger Oncogene

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Authors and Affiliations

  • Xinqi He
    • 1
    • 2
  • Yujuan Dong
    • 1
    • 3
  • Chung Wah Wu
    • 1
  • Zengren Zhao
    • 2
  • Simon S M Ng
    • 3
  • Francis K L Chan
    • 1
  • Joseph J Y Sung
    • 1
  • Jun Yu
    • 1
  1. 1.Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, Prince of Wales HospitalThe Chinese University of Hong KongShatin, NTHong Kong
  2. 2.Department of Surgery, First Affiliated HospitalHebei Medical UniversityShijiazhuangChina
  3. 3.Department of SurgeryThe Chinese University of Hong KongShatinHong Kong

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