Jiang Huijuan, Wang Yiqing, Ai Meiling, Wang Haowei, Duan Zhijiao, Wang Huanan, Zhao Li, Yu Jiang, Ding Yanqing, Wang Shuang
Department of Pathology, Southern Medical University, Nanfang Hospital, Guangzhou, China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Cell Death Dis. 2017 Jun 8;8(6):e2862. doi: 10.1038/cddis.2017.258.
Recent studies have furthered our understanding of the function of long noncoding RNAs (lncRNAs) in numerous biological processes, including cancer. This study investigated the expression of a novel lncRNA, colorectal neoplasia differentially expressed (CRNDE), in colorectal carcinoma (CRC) tissues and cells by real-time RT-PCR and in situ hybridization, and its biological function using a series of in vitro and in vivo experiments to determine its potential as a prognostic marker and therapeutic target. CRNDE was found to be upregulated in primary CRC tissues and cells (P<0.05), and the upregulation of CRNDE expression is a powerful predictor of advanced TNM stage (P<0.05) and poor prognosis for CRC patients (P=0.002). The promoting effects of CRNDE on the cell proliferation, cell cycling and metastasis of CRC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Mechanistically, it was demonstrated that CRNDE could form a functional complex with heterogeneous nuclear ribonucleoprotein U-like 2 protein (hnRNPUL2) and direct the transport of hnRNPUL2 between the nucleus and cytoplasm. hnRNPUL2 that was accumulated in the cytoplasm could interact with CRNDE both physically and functionally, increasing the stability of CRNDE RNA. Moreover, gene expression profile data showed that CRNDE depletion in cells downregulated a series of genes involved in the Ras/mitogen-activated protein kinase signaling pathways. Collectively, these findings provide novel insights into the function and mechanism of lncRNA CRNDE in the pathogenesis of CRC and highlight its potential as a therapeutic target for CRC intervention.
近期研究加深了我们对长链非编码RNA（lncRNA）在包括癌症在内的众多生物学过程中功能的理解。本研究通过实时逆转录聚合酶链反应（RT-PCR）和原位杂交检测了一种新型lncRNA——结直肠癌差异表达基因（CRNDE）在结直肠癌（CRC）组织和细胞中的表达，并通过一系列体外和体内实验研究其生物学功能，以确定其作为预后标志物和治疗靶点的潜力。结果发现，CRNDE在原发性CRC组织和细胞中上调（P<0.05），CRNDE表达上调是晚期TNM分期（P<0.05）和CRC患者预后不良（P=0.002）的有力预测指标。通过功能获得和功能丧失实验在体外和体内均证实了CRNDE对CRC细胞增殖、细胞周期和转移的促进作用。机制上，证明CRNDE可与不均一核核糖核蛋白U样2蛋白（hnRNPUL2）形成功能复合物，并指导hnRNPUL2在细胞核与细胞质之间的转运。在细胞质中积累的hnRNPUL2可在物理和功能上与CRNDE相互作用，增加CRNDE RNA的稳定性。此外，基因表达谱数据显示，细胞中CRNDE缺失下调了一系列参与Ras/丝裂原活化蛋白激酶信号通路的基因。总的来说，这些发现为lncRNA CRNDE在CRC发病机制中的功能和机制提供了新的见解，并突出了其作为CRC干预治疗靶点的潜力。
