State Key Laboratory for Oncogenes and Related Genes; Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai, China.
Cancer Res. 2014 Dec 1;74(23):6890-902. doi: 10.1158/0008-5472.CAN-14-0686. Epub 2014 Oct 2.
It is increasingly evident that long noncoding RNAs (lncRNA) have causative roles in carcinogenesis. In this study, we report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization (ISH) analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue ISH analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival. Taken together, our results identify a noncoding regulatory pathway for the CD44 oncogene, shedding new light on the basis for gastric cancer cell invasiveness.
长链非编码 RNA(lncRNA)在肿瘤发生中具有因果作用,这一点越来越明显。本研究通过全基因组微阵列和原位杂交(ISH)分析,鉴定出人类胃癌标本中异常表达的 lncRNA,报告了一种新型 lncRNA 与胃癌相关的研究结果,该 lncRNA 被命名为 GAPLINC(胃腺癌预测性长基因间非编码 RNA)。GAPLINC 是一种 924bp 的长链非编码 RNA,在胃癌组织中高表达。GAPLINC 抑制及其在胃癌细胞中的基因表达谱分析显示,细胞迁移途径发生改变,CD44 表达相关性最高。操纵 GAPLINC 的表达改变了 CD44 mRNA 的丰度,GAPLINC 对细胞迁移和增殖的影响可通过抑制 CD44 的表达而被中和。机制研究表明,GAPLINC 作为 miR211-3p 的分子诱饵调节 CD44,miR211-3p 是一种靶向 CD44 和 GAPLINC 的 microRNA。组织 ISH 分析表明,GAPLINC 过表达定义了具有极差生存预后的胃癌患者亚群。综上所述,我们的研究结果确定了 CD44 癌基因的非编码调节途径,为胃癌细胞侵袭性的基础提供了新的认识。