Genetic and Epigenetic Down-regulation of MicroRNA-212 Promotes Colorectal Tumor Metastasis via Dysregulation of MnSOD

被引：106

作者：

Meng, Xiangqi ^{[1
]}

Wu, Jiangxue ^{[1
]}

Pan, Changchuan ^{[2
]}

Wang, Hui ^{[1
]}

Ying, Xiaofang ^{[1
]}

Zhou, Yi ^{[1
]}

Yu, Hongyan ^{[1
]}

Zuo, Yufang ^{[1
]}

Pan, Zhizhong ^{[1
]}

Liu, Ran-Yi ^{[1
]}

Huang, Wenlin ^{[1
,3
]}

机构：

[1] Sun Yat Sen Univ, State Key Lab Oncol South China, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China

[2] Second Peoples Hosp Sichuan Prov, Sichuan Canc Hosp & Inst, Chengdu, Peoples R China

[3] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China

来源：

GASTROENTEROLOGY | 2013年 / 145卷 / 02期

基金：

中国国家自然科学基金; 国家高技术研究发展计划(863计划);

关键词：

Gene Expression; Epigenetic Regulation; Genetic Alteration; Colorectal Cancer; MANGANESE-SUPEROXIDE-DISMUTASE; BREAST-CANCER CELLS; MIR-212; EXPRESSION; LUNG-CANCER; LIVER; ACTIVATION; MECHANISM; APOPTOSIS; OVEREXPRESSION; INDUCTION;

D O I：

10.1053/j.gastro.2013.04.004

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：426 / +

页数：17

共 43 条

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