Long non-coding RNAs: An emerging powerhouse in the battle between life and death of tumor cells

Abstract

Long non-coding RNAs (lncRNAs) represent a class of non-protein coding transcripts longer than 200 nucleotides that have aptitude for regulating gene expression at the transcriptional, post-transcriptional or epigenetic levels. In recent years, lncRNAs, which are believed to be the largest transcript class in the transcriptomes, have emerged as important players in a variety of biological processes. Notably, the identification and characterization of numerous lncRNAs in the past decade has revealed a role for these molecules in the regulation of cancer cell survival and death. It is likely that this class of non-coding RNA constitutes a critical contributor to the assorted known or/and unknown mechanisms of intrinsic or acquired drug resistance. Moreover, the expression of lncRNAs is altered in various patho-physiological conditions, including cancer. Therefore, lncRNAs represent potentially important targets in predicting or altering the sensitivity or resistance of cancer cells to various therapies. Here, we provide an overview on the molecular functions of lncRNAs, and discuss their impact and importance in cancer development, progression, and therapeutic outcome. We also provide a perspective on how lncRNAs may alter the efficacy of cancer therapy and the promise of lncRNAs as novel therapeutic targets for overcoming chemoresistance. A better understanding of the functional roles of lncRNA in cancer can ultimately translate to the development of novel, lncRNA-based intervention strategies for the treatment or prevention of drug-resistant cancer.

Introduction

It is currently well recognized that the vast majority of the human genome is transcribed, one of the important discoveries from the Encyclopedia of DNA Elements (ENCODE) consortium (Consortium, 2012, Djebali et al., 2012). Nevertheless, according to an estimate from the latest GENCODE version 22 (http://www.gencodegenes.org), only 2% of the human genome codes for proteins, while most of the human genome (75–90%) is transcribed as non-coding RNAs (ncRNAs) (Harrow et al., 2012). Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that lack the protein-coding potential. The 200 nucleotide cut-off is a convenient length that excludes small RNAs based on RNA purification protocols (Kapranov et al., 2007). Recent high-throughput transcriptome sequencing has revealed thousands of human lncRNA genes, and the numbers of lncRNAs are expected to continue to grow (Hangauer et al., 2013). According to the lncRNA database, LNCipedia 2.0 (http://www.lncipedia.org/), 32,198 human lncRNAs sequences have been identified. The discovery of lncRNAs with multiple regulatory functions has redefined the landscape of transcriptome regulation. LncRNAs are transcribed from various genomic locations and can be classified according to their genomic location relative to protein-coding transcripts. These classifications include: (1) intragenic transcripts, which are located in sense, antisense, intronic, or gene regulatory regions, such as promoters, enhancers and UTRs; (2) bidirectional transcripts, which share the same promoter with protein-coding genes but are transcribed in the opposite direction; and (3) intergenic transcripts (also known as lincRNAs), which are located in the gene-desert regions and do not overlap with other genes (Rinn and Chang, 2012) (Fig. 1).

Unlike miRNAs whose primary role is to repress mRNA translation, lncRNAs can act as molecular scaffolds, miRNA sponges, protein decoys, and reservoirs of small ncRNAs (Shi et al., 2013b). An increasing body of evidence has demonstrated that lncRNAs participate in the regulation of a variety of biological functions that determine cell fate and impact a variety of physiological and pathological processes (Batista and Chang, 2013, Huarte and Rinn, 2010). Recent studies have also reported the involvement of lncRNAs in cancer initiation and progression through their effects on the survival or death of pre-cancerous or cancerous cells (Gutschner and Diederichs, 2012, Yuan et al., 2015), suggesting that lncRNAs may have roles as oncogenes or tumor suppressor genes (Huang et al., 2014, Yuan et al., 2015). It is likely that lncRNAs constitute critical contributors to various known or/and unknown mechanisms of intrinsic or acquired drug resistance, and are important determinants of the efficacy of anticancer therapies. Indeed, dysregulated expression of certain lncRNAs are associated with tumor progression and predict patient outcomes (Garzon et al., 2015, Wang et al., 2015b). Thus, lncRNAs constitute a potentially new group of prognostic biomarkers or therapeutic targets for cancer (Wang et al., 2015b, Yuan et al., 2015). In this review, we focus on the roles, functions and mechanisms of lncRNAs in regulating the life and death of tumor cells and their impact in cancer development, progression, and therapeutic response. The implication of lncRNAs in treating therapy-resistant cancer is also discussed.