A Novel lncRNA, LINC00460, Affects Cell Proliferation and Apoptosis by Regulating KLF2 and CUL4A Expression in Colorectal Cancer

Abstract

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.

Long noncoding RNA MAPKAPK5‐AS1 promotes colorectal cancer proliferation by partly silencing p21 expression

“…For example, lncRNA CRNDE inhibits the expression of downstream target gene DUSP5/CDKN1A by binding EZH2 and promotes the proliferation of CRC cells . In addition, Linc00460 regulates proliferation of CRC cells by recruiting EZH2 and AGO2 to regulate the downstream target gene KLF2/CUL4A . Therefore, it is necessary to further explore the causes of abnormal expression, to provide a theoretical basis and research direction for the early diagnosis and early treatment of CRC.…”

Prognostic significance of LINC00460 overexpression in solid tumours: a meta-analysis

“…These eligible studies (one nasopharyngeal carcinoma, one oesophageal squamous cell carcinoma, two colorectal cancers, 1lung adenocarcinoma, one epithelial ovarian cancer, one non-small cell lung cancer, one gastric cancer and one bladder urothelial carcinoma) with a total of 935 patients13–17 19 29–31 were enrolled in this meta-analysis according to the criteria. Additionally, the basic information and characteristics of each trial were summarised in tables 1 and 2.…”

“…Long intergenic non-protein coding RNA 460 (LINC00460) is located at chromosome 13q33.2 and transcribed into a 935nt in length transcript 13. Abnormal expression of LINC00460 was found in various cancers, including nasopharyngeal carcinoma,14 oesophageal squamous cell carcinoma,15 colorectal cancer,16–18 lung adenocarcinoma,13 non-small cell lung cancer19–21 and so on. Overexpression of LINC00460 has been shown to be associated with clinicopathological parameters and a poor prognosis in various cancers.…”

Unveiling the druggable RNA targets and small molecule therapeutics

“…There is also the mostly unexplored potential of targeting novel RNA species, such as circular RNAs, 205 antisense RNAs 206 and lncRNAs. 207 In addition, RNA-mediated interactions often dysregulated in variety of human disorders, 208 further widen the pallete of druggable targets. Aberrant interactions of RNA with proteins is a well-recognized factor that leads to the RNA gain-of-function mechanism that underlines repeat expansion disorders as discussed.…”