Genetic and Epigenetic Down-regulation of MicroRNA-212 Promotes Colorectal Tumor Metastasis via Dysregulation of MnSOD
Genetic and Epigenetic Down-regulation of MicroRNA-212 Promotes Colorectal Tumor Metastasis via Dysregulation of MnSOD
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MicroRNA-212 的遗传和表观遗传下调通过 MnSOD 失调促进结直肠肿瘤转移
DOI：
10.1053/j.gastro.2013.04.004
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发表时间：
2013-08-01
期刊：
影响因子：
29.4
通讯作者：
Huang, Wenlin
中科院分区：
文献类型：
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作者：
Meng, Xiangqi;Wu, Jiangxue;Huang, Wenlin
背景与目的：microRNAs （miRNAs）功能的改变与结直肠癌（CRC）有关。miR-212是从一个非蛋白编码基因的稳定内含子转录而来，据报道在不同的肿瘤类型中被下调。我们研究了miR-212在结直肠癌发生和发展中的作用。方法：我们通过实时聚合酶链反应（PCR）分析结直肠癌细胞系和180对肿瘤样本及周围健康组织中miR-212的表达。我们在结直肠癌细胞系中过表达和敲低miR-212，并评估其体外效应。我们还研究了miR-212过表达对裸鼠HCT116细胞生长的肿瘤转移的影响。结果：miR-212的过表达抑制了CRC细胞在体外的迁移和侵袭以及体内肝内和肺转移的形成。我们确定锰超氧化物歧化酶（MnSOD）信使RNA是miR-212的直接靶点，并观察到结直肠肿瘤样本中miR-212与MnSOD蛋白水平呈负相关。MnSOD在CRC细胞中下调上皮标记物和上调间充质标记物是必需的，表明它促进了上皮-间充质转化。过表达miR-212可降低MnSOD水平，阻断上皮-间质转化过程。杂合性缺失和启动子超甲基化都导致miR-212的下调。miR-212水平的降低与更具侵袭性的肿瘤表型和较短的患者无病生存期相关（P = 0.0045；总生存期，P = 0.0015）。结论：miR-212在人类结直肠癌组织中通过遗传和表观遗传机制下调。miR-212可能通过靶向MnSOD信使RNA阻止肿瘤进展；miR-212的减少可能是结直肠癌患者的预后标志。miR-212和MnSOD也可能是癌症的治疗靶点。
BACKGROUND & AIMS: Altered functions of microRNAs (miRNAs) have been associated with colorectal cancer (CRC). miR-212 is transcribed from a stable intron of a non-protein coding gene, and is reportedly down-regulated in different tumor types. We investigated the role of miR-212 in colorectal carcinogenesis and progression. METHODS: We analyzed the expression of miR-212 by real-time polymerase chain reaction (PCR) analysis of colorectal cell lines and 180 paired tumor samples and surrounding healthy tissue. We overexpressed and knocked down miR-212 in CRC cell lines and assessed the in vitro effects. We also studied the effects of miR-212 overexpression on metastasis of tumors grown from HCT116 cells in nude mice. RESULTS: Overexpression of miR-212 inhibited CRC cell migration and invasion in vitro and formation of intrahepatic and pulmonary metastasis in vivo. We identified manganese superoxide dismutase (MnSOD) messenger RNA as a direct target of miR-212, and observed an inverse correlation between the level of miR-212 and MnSOD protein in colorectal tumor samples. MnSOD was required for down-regulation of epithelial markers and up-regulation of mesenchymal markers in CRC cells, indicating that it promoted the epithelial-mesenchymal transition. Overexpression of miR-212 reduced the levels of MnSOD to block the epithelial-mesenchymal transition process. Loss of heterozygosity and promoter hypermethylation each contributed to the down-regulation of miR-212. Reduced levels of miR-212 were associated with a more aggressive tumor phenotype and short disease-free survival times of patients (P = .0045; overall survival, P = .0015). CONCLUSIONS: miR-212 is down-regulated in human CRC tissues via genetic and epigenetic mechanisms. miR-212 might prevent tumor progression by targeting MnSOD messenger RNA; reduction of miR-212 could be a prognostic marker for patients with CRC. miR-212 and MnSOD might also be therapeutic targets for cancer.