Invited reviewLong non-coding RNAs: An emerging powerhouse in the battle between life and death of tumor cells
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.
Section snippets
Multiple roles of lncRNAs in the regulation of gene expression
LncRNAs have the following common features (Cabili et al., 2011, Derrien et al., 2012, Djebali et al., 2012, Wapinski and Chang, 2011): (1) their transcription is mediated via RNA polymerase II; (2) they are capped, polyadenylated, and spliced similar to protein-coding mRNAs; (3) they are regulated by those well-established transcription factors; and (4) they are poorly conserved at the sequence level. Compared to mRNAs, lncRNAs have a relatively low expression level and show a much more
Impact of lncRNAs in tumor development and progression
Cancer cells acquire the following hallmarks in the process of human cancer development and progression: (1) sustaining proliferative signaling, (2) evading growth suppressors, (3) resisting cell death, (4) enabling replicative immortality, (5) inducing angiogenesis, and, (6) activating invasion and metastasis (Hanahan and Weinberg, 2011). Although cancer consists of a heterogeneous group of diseases, one of the common features is the existence of abnormal cells that grow beyond their natural
LncRNA-mediated modulation of tumor cell sensitivity/resistance to therapeutic intervention
As the roles and functions of lncRNAs impact a variety of signaling pathways involved in regulation of cell survival or death, it is conceivable that these non-coding transcripts may also alter the efficacy of anticancer therapeutics, which are aimed at eradicating tumor cells or inhibiting their cellular growth and proliferation. Emerging evidence has suggested that dysregulated expression of lncRNAs may constitute a novel class of cancer drug resistance, a major obstacle for successful cancer
Conclusions and perspective
The aim of the current review has been to provide an overview on how lncRNAs may impact the therapeutic outcome of cancer treatment through regulation of the expression of various genes implicated in tumor cell survival and death and on the potential of lncRNAs as novel targets for circumventing chemotherapy resistance. With the availability and application of high-throughput transcriptome sequencing technology and computational biology, numerous lncRNAs have been identified and characterized
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
The study was supported by grants from the National Natural Science Foundation of China (81370456), the National Scholarship Fund of China (201408440139), the Natural Science Foundation of Guangdong Province (2014A030311015) and the Foundation for Distinguished Talents in Higher Education of Guangdong (GK1318).
The authors sincerely thank Dr. Megan Young for copyediting this manuscript.
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