Lee Hyun-Sung, Lee Kwanbok, Jang Hee-Jin, Lee Geon Kook, Park Jong-Lyul, Kim Seon-Young, Kim Sang-Bae, Johnson Betty H, Zo Jae Iii, Lee Ju-Seog, Lee Yong Sun
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, 410-769, Korea.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Oncotarget. 2014 Jun 15;5(11):3472-81. doi: 10.18632/oncotarget.1927.
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.
nc886（=vtRNA2-1或pre-miR-886）是一种最近发现的非编码RNA，它是一种细胞内蛋白激酶RNA激活的蛋白激酶（PKR）配体和抑制剂。仅基于其表达模式和基因组位点，nc886被认为是一种肿瘤抑制因子。在本报告中，我们提供了充分的证据表明nc886是食管鳞状细胞癌（ESCC）中一种假定的肿瘤抑制因子。在84例ESCC患者的配对标本中，肿瘤组织中nc886的表达明显低于其正常相邻组织。更重要的是，nc886表达降低与患者无复发生存期缩短显著相关。nc886的抑制是由其启动子的CpG高甲基化介导的，这在ESCC肿瘤中其与nc886表达的显著负相关以及其启动子去甲基化后nc886的诱导表达中得到了证实。敲低nc886并随之激活PKR可诱导FOS和MYC癌基因以及一些包括致癌性NF-κB在内的炎症基因。当异位表达时，nc886抑制ESCC细胞的增殖，进一步证明nc886可能是一种肿瘤抑制因子。所有这些发现表明nc886是一种新的假定肿瘤抑制因子，它在ESCC中通过表观遗传沉默并调节癌基因的表达。
