MicroRNA-218 Inhibits Cell Cycle Progression and Promotes Apoptosis in Colon Cancer by Downregulating BMI1 Polycomb Ring Finger Oncogene
MicroRNA-218 Inhibits Cell Cycle Progression and Promotes Apoptosis in Colon Cancer by Downregulating BMI1 Polycomb Ring Finger Oncogene
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MicroRNA-218 通过下调 BMI1 多梳环指癌基因抑制结肠癌细胞周期进程并促进细胞凋亡
DOI：
10.2119/molmed.2012.00304
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发表时间：
2012-12-01
影响因子：
5.7
通讯作者：
Yu, Jun
中科院分区：
文献类型：
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作者：
He, Xinqi;Dong, Yujuan;Yu, Jun
失调的miRNAs参与结直肠癌的发生在这项研究中，miR-218被发现在人类结直肠癌（CRC）中下调。相对于正常结肠组织，miR-218在所有五种结肠癌细胞（Caco 2、HT 29、SW 620、HCT 116和LoVo）中沉默或下调。46例大肠癌组织中miR-218的表达显著低于癌旁正常组织（P < 0.001）。预测了miR-218的潜在靶基因，并确定多梳环指癌基因BMI 1（polycomb ring finger oncogene，BMI-1）为潜在靶基因之一。与邻近正常组织相比，在CRC肿瘤中检测到BMI-1的上调（P < 0.001），并且在所有五种结肠癌细胞系中检测到BMI-1的上调。miR-218转染结肠癌细胞系（HCT 116，HT 29）后，BMI-1 3′非翻译区（3′UTR）野生型构建体的荧光素酶活性显著降低（P < 0.001），而突变体BMI-1 3′UTR构建体中未见此效应，表明miR-218与BMI-1之间存在直接且特异的相互作用。miR-218在HCT 116和HT 29细胞中的异位表达抑制BMI-1 mRNA和蛋白表达。此外，miR-218抑制BMI-1下游细胞周期蛋白依赖性激酶4（一种细胞周期调节因子）的蛋白表达，同时上调p53的蛋白表达。miR-218诱导细胞凋亡（P < 0.01），抑制细胞增殖（P < 0.05），促进细胞周期阻滞于G2期（P < 0.01）。总之，miR-218通过下调BMI-1抑制细胞增殖和周期进展并促进细胞凋亡，在CRC发展中起关键作用。
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.