Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
Department of Computer Science, University of Central Florida, Orlando, FL 32816, USA.
Sci Adv. 2017 May 3;3(5):e1602505. doi: 10.1126/sciadv.1602505. eCollection 2017 May.
Molecular mechanisms by which long noncoding RNA (lncRNA) molecules may influence cancerous condition are poorly understood. The aberrant expression of lncRNA, encoded within the drosophila gene homolog intron, is correlated with a variety of cancers, including human melanomas. We demonstrate by SHAPE-seq and dChIRP that RNA secondary structure has a core pseudoknotted domain. This lncRNA interacts with the intronic regions of six pre-mRNAs: , , , , , and , all of which have cancer-related functions. Hemizygous knockout of by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 in melanoma cells significantly decreases lncRNA levels, simultaneously decreases the levels of its interacting pre-mRNA molecules, and decreases anchorage-independent growth rate of cells and the rate of in vivo tumor growth in mouse xenografts. These results provide the first demonstration of an lncRNA's three-dimensional coordinating role in facilitating cancer-related gene expression in human melanomas.
长链非编码 RNA(lncRNA)分子影响癌症状态的分子机制尚未完全阐明。果蝇基因同源物内含子编码的 lncRNA 的异常表达与多种癌症相关,包括人类黑色素瘤。我们通过 SHAPE-seq 和 dChIRP 证明了 RNA 的二级结构具有核心假结结构域。这种 lncRNA 与六个前体 mRNA 的内含子区域相互作用: , , , , , 和 ,所有这些都具有与癌症相关的功能。在黑色素瘤细胞中通过 CRISPR(成簇的规律间隔的短回文重复序列)/Cas9 对半敲除 显著降低了 lncRNA 的水平,同时降低了与其相互作用的前体 mRNA 分子的水平,并降低了细胞的无锚定生长速率和体内肿瘤生长速度在小鼠异种移植中。这些结果首次证明了 lncRNA 在促进人类黑色素瘤中与癌症相关的基因表达中的三维协调作用。