Advances in technology for RNA profiling, coupled with computational analysis of functional elements in the human genome led by the Encyclopedia of DNA Elements (ENCODE) project, have led to the surprising conclusion that at least 75 percent of the human genome is transcribed in at least one cell type. The majority of these transcripts can be classified as long non-coding RNA (1). Long non-coding RNAs (lncRNAs) are defined as non-protein-coding RNA molecules that are at least 200 nucleotides in length (2). Although scientists previously accepted the theory that approximately 98 percent of the human genome contained so-called “junk” DNA, based on the assumption that proteins are the primary cellular players, research within the past decade has placed non-coding RNA on par with protein in functional significance. As lncRNA is present not only in cells and tissues, but also in exosomes and microvesicles, it has great potential for both helping us unravel underlying mechanisms of diseases as well as use in liquid biopsies.
Recent studies of lncRNAs indicate that they play an important role in tumor proliferation, migration and angiogenesis. The most extensively characterized lncRNA to date is the HOX transcript antisense RNA (HOTAIR). Expression of HOTAIR is elevated in breast, colon, lung and pancreatic cancer and is associated with metastasis and poor prognosis (3). The HOTAIR transcript interacts with chromatin remodeling proteins and recruits chromatin modifiers to repress transcription. lncRNAs have also played a role in tumor suppression. The lncRNA LEIGC was found to be expressed at lower levels in human gastric cancer compared to adjacent normal tissue (4). This same study found that overexpression of LEIGC suppressed gastric cancer cell proliferation, while knockdown of LEIGC promoted tumor progression in mice. Taken together, these studies indicate that lncRNAs are not simply markers of tumorigenesis but play an important role in cancer proliferation and progression. The observation that HOTAIR is over-expressed in multiple cancer types also provides promise for therapeutic intervention that is applicable to multiple tumor types.
The growth in lncRNA research will likely reveal the importance of lncRNA in multiple pathways, from tissue development and differentiation to applications involving regulatory roles in cancer development and proliferation. Multiple challenges remain for scientists to exploit lncRNA fully for clinical applications like liquid biopsies. Although the technology exists to identify differentially expressed lncRNAs, sophisticated data analysis and interpretation are essential for extracting meaningful conclusions. Network analysis can provide disease associations and suggest further avenues for study. Additionally, although the therapeutic value of targeting lncRNA is apparent, novel approaches will need to be employed for successful drug discovery. Although the obstacles are significant, lncRNAs represent a rich opportunity for discovery in a former wasteland of “junk”.
1. Djebali, S. et al. (2012) Landscape of transcription in human cells. Nature 489, 101.
2. Perkel, J.M. (2013) Visiting “noncodarnia”. Biotechniques 54, 301.
3. Loewen, G. et al. lincRNA HOTAIR as a novel promoter of cancer progression. J. Can. Res. Updates 3, 134.
4. Han, Y. et al. (2014) LEIGC long non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition. BMC Cancer 14, 932.