The power of long non-coding RNAs
The cells lining the adult intestine are continuously renewing themselves. A biochemical pathway, Wnt, lies at the heart of the crucial switch – when the cells stop dividing and differentiate to become a specialised cell. Mutations that cause faults in the molecular outcome of the pathway can cause colorectal cancer. The WNTLINCS (Identification and functional and mechanistic characterization of Wnt-regulated long intergenic non-coding RNAs) project has identified novel Wnt target genes and explored how they are regulated by the pathway. ‘Understanding how the pathway regulates them and elucidating how these target genes impact intestinal physiology and disease is crucial in designing novel diagnostic tools and therapeutic approaches.’ explains Dr Pantelis Hatzis, project coordinator at the Biomedical Sciences Research Center Alexander Fleming. Importance of lncRNAs in sickness and health Researchers looked specifically at a class of newly identified genes, long non-coding RNAs (lncRNAs). Although thought to be highly important in cell health and disease, only a small number have been characterised, out of tens of thousands potentially out there. WNTLINCS used cutting-edge technologies to address challenges such as the naturally low levels of lncRNAs in systems, sometimes lower than ten molecules in one cell! The researches focused on WNT-regulated long intergenic non-coding RNA 1 (WiNTRLINC1), which is a direct positive target of the Wnt pathway and is necessary for the viability of colorectal cancer cells. To do so, WiNTRLINC1 molecules cause the formation of chromosome loop to come into contact with the regulatory regions of another gene close by, ASCL2. Links to cancer The ASCL2 gene is part of the system that controls the fate of stem cells in the intestine and, with WiNTRLINC1, forms a feedforward regulatory loop, which is dramatically amplified in colorectal cancer. WNTLINCS researchers have also found that WiNTRLINC1-ASCL2 control is amplified in other forms of cancer and is involved with a tendency to develop the disease. ‘We are conducting experiments aimed at elucidating the WiNTRLINC1-ASCL2 contribution to non-intestinal carcinogenesis.’ says Dr Hatzis. Another two lncRNAs strongly implicated in cancer development are WiNTRLNC2 and WiNTRLINC3. Like WiNTRLINC1, they are necessary for the survival of colorectal cancer cells. Absence of the two lncRNAs causes changes in the fate of stem cells. Dr Hatzis talks about ongoing investigations ‘We are currently carrying out experiments to decipher the mechanistic basis behind the dramatic phenotypes caused by the absence of WiNTRLNC2 and WiNTRLINC3 in colorectal cancer cells and studying their role in carcinogenesis in other tissues.’ Future of personalised lncRNA therapy in the clinic Project researchers believe that some of the lncRNAs they have worked on could turn into promising targets for diagnosis and therapy in a personalised medicine setting. ‘WiNTRLINC1 for example is overexpressed in colorectal cancer and, through its actions on ASCL2, is putatively involved in cancer stem cell maintenance and expansion.’ explains Dr Hatzis. Moreover, WiNTRLINC1 in other tissues is expressed only in some patients and only in cancerous tissue. ‘This would make it an ideal candidate for personalised diagnostic and therapeutic applications.’ The potential of lncRNAs in personalised medicine is evident from the interest expressed by biotech companies. As for the time frame, Dr Hatzis is optimistic ‘we could envisage that, given the right circumstances and sufficient interest from the biotech and pharmaceutical sector, some aspects of our work could have clinical applications within years rather than decades.’
Keywords
Long non-coding RNAs, personalised, colorectal cancer, Wnt, WNTLINCS, ASCL2
