Epigenetic silencing of the non-coding RNA nc886 provokes oncogenes during human esophageal tumorigenesis.
Epigenetic silencing of the non-coding RNA nc886 provokes oncogenes during human esophageal tumorigenesis.
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DOI：
10.18632/oncotarget.1927
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发表时间：
2014-06-15
期刊：
影响因子：
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通讯作者：
Lee YS
中科院分区：
文献类型：
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作者：
Lee HS;Lee K;Jang HJ;Lee GK;Park JL;Kim SY;Kim SB;Johnson BH;Zo JI;Lee JS;Lee YS
nc 886（= vtRNA 2 -1或pre-miR-886）是最近发现的非编码RNA，是细胞PKR（蛋白激酶RNA激活）配体和阻遏物。仅基于其表达模式和基因组位点，已经认为nc 886是肿瘤抑制因子。在本报告中，我们提供了足够的证据表明nc 886是食管鳞状细胞癌（ESCC）的一个假定的肿瘤抑制因子。在84对ESCC患者的标本中，nc 886在肿瘤中的表达显著低于其正常相邻组织。更重要的是，nc 886的表达降低与患者的无复发生存期缩短显著相关。nc 886的抑制是由其启动子的CpG超甲基化介导的，如通过其与ESCC肿瘤中nc 886表达的显著负相关性以及通过其启动子去甲基化后nc 886的诱导表达所证明的。nc 886的敲低和随后的PKR活化诱导FOS和MYC癌基因以及一些炎性基因，包括致癌NF-κB。当异位表达时，nc 886抑制ESCC细胞的增殖，进一步证明nc 886可能是肿瘤抑制因子。所有这些研究结果暗示nc 886作为一种新的，推定的肿瘤抑制基因，是表观遗传沉默和调节癌基因的表达在食管鳞癌。
nc886 (= vtRNA2-1 or pre-miR-886) is a recently discovered noncoding RNA that is a cellular PKR (Protein Kinase RNA-activated) ligand and repressor. nc886 has been suggested to be a tumor suppressor, solely based on its expression pattern and genomic locus. In this report, we have provided sufficient evidence that nc886 is a putative tumor suppressor in esophageal squamous cell carcinoma (ESCC). In 84 paired specimens from ESCC patients, nc886 expression is significantly lower in tumors than their normal adjacent tissues. More importantly, decreased expression of nc886 is significantly associated with shorter recurrence-free survival of the patients. Suppression of nc886 is mediated by CpG hypermethylation of its promoter, as evidenced by its significant negative correlation to nc886 expression in ESCC tumors and by induced expression of nc886 upon demethylation of its promoter. Knockdown of nc886 and consequent PKR activation induce FOS and MYC oncogenes as well as some inflammatory genes including oncogenic NF-κB. When ectopically expressed, nc886 inhibits proliferation of ESCC cells, further demonstrating that nc886 could be a tumor suppressor. All these findings implicate nc886 as a novel, putative tumor suppressor that is epigenetically silenced and regulates the expression of oncogenes in ESCC.