Abstract
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.
Highlights
Colorectal carcinoma (CRC) is the third leading cause of cancer-related deaths worldwide, and its incidence is on the rise.[1]
The expression level of colorectal neoplasia differentially expressed (CRNDE)-h transcript was upregulated in the plasma of CRC patients, and the expression levels of this transcript alone have shown a sensitivity of 87% and specificity of 93% for predicting the presence of CRC.[11]
It is well known that long noncoding RNAs (lncRNAs) are an important player in cancer biology, typically causing the aberrant expression of gene products that contribute to the progression of a number of human cancers.[7,20]
Summary
Colorectal carcinoma (CRC) is the third leading cause of cancer-related deaths worldwide, and its incidence is on the rise.[1]. The expression level of CRNDE-h transcript was upregulated in the plasma of CRC patients, and the expression levels of this transcript alone have shown a sensitivity of 87% and specificity of 93% for predicting the presence of CRC.[11] In addition to CRC, CRNDE overexpression has been observed in many other solid tumors and lymphocytic leukemias.[12] In glioma, CRNDE is the most highly expressed lncRNA,[12,13] and it has been shown to affect the malignant biological characteristics of glioma stem cells.[14] In ovarian cancer, elevated levels of CRNDE were found to be a negative prognostic factor, increasing the risk of death and recurrence in ovarian cancer patients treated with platinum compounds and taxanes.[15] Very recently, a study has shown that increased expression of CRNDE is correlated with a poor prognosis in CRC.[16] Collectively, the current evidence suggests that CRNDE overexpression appears to have a key role in tumorigenesis. Our findings provide novel insights into the function and mechanisms of CRNDE in CRC pathogenesis and a potential therapeutic target for CRC intervention
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