Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

Abstract

Long non-coding RNAs (lncRNAs) are a class of newly identified non-coding RNA molecules that are emerging as key regulators of tumor initiation and development. Colorectal cancer (CRC) remains a major health problem worldwide, and there remains a need to further refine the current screening approaches as well as provide tailored diagnostic and therapeutic approaches. Multiple dysregulated lncRNAs participate in tumorigenesis through a variety of molecular mechanisms, and various regulatory factors frequently contribute to the aberrant expression of lncRNAs in CRC, thereby allowing malignant transformation. Additionally, the association of dysregulated lncRNAs with specific developmental stages and clinical outcomes indicates their potential as strong diagnostic and prognostic predictors as well as therapeutic targets. Here we provide a brief overview of the known functions of CRC-associated lncRNAs, describe some potential molecular mechanisms that underlie changes in lncRNA expression in CRC, and attempt to uncover their clinical and therapeutic potential. Keywords: colorectal cancer; diagnosis; dysregulation; long non-coding RNA; prognosis High-throughput genome-scale studies have demonstrated that more than 93% of the DNA sequences in the human genome are actively transcribed. 1 However, only approximately 5-10% of the sequences are stably transcribed into mRNA or non-coding RNA (ncRNA). Genome tiling arrays have revealed that the amount of non-coding sequence is at least four times larger than the amount of coding sequence, which indicates that only 1% of the human genome is composed of protein-coding genes and the remaining 4-9% is transcribed into ncRNAs. 2 Therefore, ncRNAs constitute a very large proportion of the total RNA molecules.The function and clinical significance of short regulatory ncRNAs, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), were elucidated first, 3 and the regulatory roles of miRNAs have been broadly recognized in almost all physiological and pathological processes in the body, including carcinogenesis. 4 For example, we previously reported that MIR95 promotes cell proliferation and targets sorting nexin 1 in human colorectal carcinoma; 5 moreover, in colorectal cancer (CRC) patients, the plasma levels of MIR29a and MIR92a are significantly upregulated and the plasma levels of MIR601 and MIR760 are significantly downregulated; thus the levels of these miRNAs have good diagnostic value for CRC screening. 6,7 According to their transcript size, ncRNAs are grouped into two major classes: (i) small ncRNAs with transcripts o200 nucleotides (nt; eg, aforementioned siRNAs and miRNAs, Piwi-interacting RNAs, and some retrotransposon-derived RNAs) and (ii) long non-coding RNAs (lncRNAs), this class includes five broad categories: sense, antisense, bidirectional, intronic, and intergenic, based on the proximity between neighboring transcripts. 8 For a time, lncRNAs was commonly defined as a proteincoding transcripts that is 4200 nt. 9 However, this definition is arbitrary and ...

Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

“…In 2001, lncRNA dysregulation was identified in CRC in the setting of loss of imprinting of the long QT intronic transcript 1 (LIT1/KCNQ1OT1) 283 . Emerging evidence indicates that the aberrant expression of lncRNAs may have a functional role in CRC pathogenesis which would have obvious clinical implications 284 . For instance, the oncogenic lncRNA, HOX Antisense Intergenic RNA (HOTAIR) is a 2158 bp gene residing in the mammalian HOXC locus on chromosome 12q13.13.…”

Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression

“…LncRNAs, which are mRNA-like transcripts longer than 200 bases that lack protein-coding capability, are reported to be frequently aberrantly expressed in diverse pathological processes in many species [6]. Increasing evidence suggests that lncRNAs serve as key regulators of tumour initiation and development.…”

The RNA-binding protein ESRP1 promotes human colorectal cancer progression

“…Colorectal carcinogenesis is a complex process in which the activation of oncogenes and inactivation of tumor suppressor genes affect several critical cancer-related pathways [2, 3]. Recent advances in the field of CRC have highlighted several new key regulators of tumour initiation and progression, including short and long regulatory non-coding RNAs [4, 5]. Dysregulation in these molecules may alter many gene regulatory networks at the transcriptional, post-transcriptional or epigenetic level leading to cancer cell transformation.…”