The role of long noncoding RNAs in cancer: the dark matter matters

Sequencing technology has facilitated a new era of cancer research, especially in cancer genomics. Using next-generation sequencing, thousands of long noncoding RNAs (lncRNAs) have been identified as abnormally altered in the cancer genome or differentially expressed in tumor tissues. These lncRNAs are associated with imbalanced gene regulation and aberrant biological processes that contribute to malignant transformation. The functions and therapeutic potential of cancer-related lncRNAs have attracted considerable interest in the past few years. Although few lncRNAs have been well-characterized, researchers have recently made impressive progress in understanding lncRNAs and their novel functions, such as regulation of gene expression, metabolism and DNA repair. These latest findings reinforce the crucial roles of lncRNAs in cancer initiation and development, as well as their possible clinical applications.

Introduction

The human genome contains thousands of noncoding regions, which were considered ‘junk DNA’ for decades because of a lack of evidence for their transcription and failure to encode proteins. Recent technological advances, like tiling arrays and next-generation sequencing, revealed that the human genome, including the noncoding regions, is pervasively transcribed. Up to 75% of the human genome can be transcribed into RNAs, whereas less than 2% encodes proteins [1]. Much of the human transcriptome is composed of noncoding RNAs, including long noncoding RNAs (lncRNAs), one of the major subtypes. RNA transcripts >200 nucleotides without apparent protein-coding potential are considered lncRNAs. After the initial cloning of lncRNA genes such as H19 and Xist from cDNA libraries, a large number of lncRNA genes have been identified genome-wide [2, 3]. According to the latest GENCODE consortium release (version 26), 15,787 lncRNA genes have been identified in the human genome, yielding 27,720 lncRNA transcripts. Although lncRNAs are widely expressed in human tissues, they are under weaker selective constraints during evolution, and are less abundant and more tissue-specific than protein-coding genes [4].

Once known as genomic ‘dark matter,’ current evidence indicates that lncRNAs participate in several biological processes (Figure 1). Acting as transcription signal activators, decoys, guides, or scaffolds for their binding partners are typical molecular mechanisms of lncRNAs [5]. They can regulate transcriptional activity in a cis or trans manner, by recruiting transcription factors or epigenetic modification complexes [6]. LncRNAs are also important for posttranscriptional regulation. They can modulate alternative splicing [7], undergo processing to small RNAs [8], regulate mRNA degradation and translation [9, 10], or act as microRNA sponges (competitive endogenous RNAs) [11]. Moreover, a special subset of lncRNAs, enhancer RNAs, are transcribed from enhancer region or a gene neighboring locus and influence gene transcription [12]. In addition to their physiologic roles, lncRNAs are associated with diseases especially with cancer. For example, HOTAIR [13], PCAT1 [14], MALAT1 [15] and FAL1 [16] have been implicated in a variety of human cancers.

Despite the large number of lncRNAs in the human genome, few have been well-characterized. The majority of lncRNA genes, especially cancer-related lncRNAs, need to be annotated and further explored. Here, we review recent research into the roles of lncRNAs in cancer (Table 1), and provide an overview of newly annotated lncRNAs and their potential in cancer diagnosis and therapy.