Aberrant Methylation-Mediated Silencing of lncRNA MEG3 Functions as a ceRNA in Esophageal Cancer
Aberrant Methylation-Mediated Silencing of lncRNA MEG3 Functions as a ceRNA in Esophageal Cancer
复制标题
lncRNA MEG3 异常甲基化介导的沉默在食管癌中充当 ceRNA。
DOI：
10.1158/1541-7786.mcr-16-0385
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发表时间：
2017-07-01
影响因子：
5.2
通讯作者：
Guo, Wei
中科院分区：
文献类型：
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作者：
Dong, Zhiming;Zhang, Aili;Guo, Wei
母体表达基因3（MEG 3）是一种长链非编码RNA（lncRNA），具有肿瘤抑制特性，并且其表达在几种人类肿瘤中丢失。然而，其在食管鳞状细胞癌（ESCC）肿瘤发生中的生物学作用尚不清楚。本研究旨在探讨MEG 3在食管癌细胞和ESCC临床标本中的作用和甲基化状态，并进一步观察MEG 3竞争性内源性RNA（ceRNA）活性在ESCC发病和发展中的作用。MEG 3在食管癌细胞和食管鳞癌组织中表达显著下调，经DNA甲基转移酶抑制剂5-Aza-dC处理后，MEG 3在食管癌细胞中的表达水平显著升高。MEG 3的上调导致癌细胞的增殖和侵袭性的抑制。MEG 3的异常启动子超甲基化表明其表达沉默。此外，MEG 3作为ceRNA通过结合hsa-miR-9来调节E-cadherin和FOXO 1的表达。miR-9在食管癌细胞系和食管鳞癌组织中表达上调，miR-9促进食管癌细胞增殖和侵袭。最后，MEG 3的下调和甲基化与ESCC患者的生存率相关。意义：MEG 3作为一种肿瘤抑制性lncRNA发挥作用，异常的启动子甲基化是ESCC中MEG 3基因沉默的关键。此外，MEG 3作为一种ceRNA，通过竞争性结合miR-9调控E-cadherin和FOXO 1的表达，可作为预测ESCC患者病情进展和预后的潜在生物标志物。
Maternally expressed gene 3 (MEG3), a long non-coding RNA (lncRNA), has tumor-suppressor properties and its expression is lost in several human tumors. However, its biological role in esophageal squamous cell carcinoma (ESCC) tumorigenesis is poorly defined. The present study determined the role and methylation status of MEG3 in esophageal cancer cells and ESCC clinical specimens, and further observed the competing endogenous RNA (ceRNA) activity of MEG3 in the pathogenesis and development of ESCC. Significant downregulation of MEG3 was detected in esophageal cancer cells and ESCC tissues and the expression level of MEG3 was significantly increased in cancer cells after treated with the DNA methyltransferase inhibitor 5-Aza-dC. Upregulation of MEG3 led to the inhibition of proliferation and invasiveness of the cancer cells. The aberrant promoter hypermethylation of MEG3 indicates silencing of its expression. Furthermore, MEG3 acts as a ceRNA to regulate the expression of E-cadherin and FOXO1 by binding hsa-miR-9. Upregulation of miR-9 was detected in esophageal cancer cell lines and ESCC tissues, and miR-9 promoted esophageal cancer cell proliferation and invasion. Finally, downregulation and hypermethylation of MEG3 was associated with ESCC patients' survival.Implications: MEG3 functions as a tumor-suppressive lncRNA and aberrant promoter hypermethylation is critical for MEG3 gene silencing in ESCC. In addition, MEG3 acts as a ceRNA to regulate expression of E-cadherin and FOXO1 by competitively binding miR-9 and may be used as a potential biomarker in predicting ESCC patients' progression and prognosis.