title: MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene.
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.
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xinqi
authors.initials: X
authors.lastname: He
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Dong
authors.forename: Chung Wah
authors.initials: CW
authors.lastname: Wu
authors.forename: Zengren
authors.initials: Z
authors.lastname: Zhao
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
authors.forename: Francis K L
authors.initials: FK
authors.lastname: Chan
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D015203:Reproducibility of Results; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C069077:BMI1 protein, human; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D063150:Polycomb Repressive Complex 1