Emerging evidence has proven that long noncoding RNAs (lncRNAs) play important roles in human colorectal cancer (CRC) biology, although few lncRNAs have been characterized in CRC. Therefore, the functional significance of lncRNAs in the malignant progression of CRC still needs to be further explored. In this study, through analyzing TCGA RNA sequencing data and other publicly available microarray data, we found a novel lncRNA, LINC00460, whose expression was significantly upregulated in CRC tissues compared to adjacent normal tissues. Consistently, real-time qPCR results also verified that LINC00460 was overexpressed in CRC tissues and cells. Furthermore, high LINC00460 expression levels in CRC specimens were correlated with larger tumor size, advanced tumor stage, lymph node metastasis and shorter overall survival. In vitro and in vivo assays of LINC00460 alterations revealed a complex integrated phenotype affecting cell growth and apoptosis. Mechanistically, LINC00460 repressed Krüppel-like factor 2 (KLF2) transcription by binding to enhancer of zeste homolog 2 (EZH2). LINC00460 also functioned as a molecular sponge for miR-149-5p, antagonizing its ability to repress cullin 4A (CUL4A) protein translation. Taken together, our findings support a model in which the LINC00460/EZH2/KLF2 and LINC00460/miR-149-5p/CUL4A crosstalk serve as critical effectors in CRC tumorigenesis and progression, suggesting new therapeutic directions in CRC.

新兴证据已经证明，尽管很少有lncRNA在CRC中得到表征，但长的非编码RNA（lncRNA）在人大肠癌（CRC）生物学中起着重要作用。因此，lncRNAs在CRC恶性进展中的功能意义仍需进一步探讨。在这项研究中，通过分析TCGA RNA测序数据和其他可公开获得的微阵列数据，我们发现了一种新型的lncRNA LINC00460，与邻近的正常组织相比，其在CRC组织中的表达明显上调。一致地，实时定量PCR结果也证实LINC00460在CRC组织和细胞中过表达。此外，CRC标本中的LINC00460高表达水平与更大的肿瘤大小，晚期肿瘤分期，淋巴结转移和较短的总生存期相关。LINC00460改变的体外和体内测定揭示了影响细胞生长和凋亡的复杂整合表型。从机理上讲，LINC00460通过与zeste同源物2（EZH2）的增强子结合而抑制了Krüppel样因子2（KLF2）的转录。LINC00460还充当miR-149-5p的分子海绵，拮抗其抑制cullin 4A（CUL4A）蛋白翻译的能力。综上所述，我们的发现支持一种模型，其中LINC00460 / EZH2 / KLF2和LINC00460 / miR-149-5p / CUL4A串扰在CRC肿瘤发生和发展中起关键作用，这为CRC提出了新的治疗方向。