Non-coding landscapes of colorectal cancer

Abstract

For two decades Vogelstein’s model has been the paradigm for describing the sequence of molecular changes within protein-coding genes that would lead to overt colorectal cancer (CRC). This model is now too simplistic in the light of recent studies, which have shown that our genome is pervasively transcribed in RNAs other than mRNAs, denominated non-coding RNAs (ncRNAs). The discovery that mutations in genes encoding these RNAs [i.e., microRNAs (miRNAs), long non-coding RNAs, and circular RNAs] are causally involved in cancer phenotypes has profoundly modified our vision of tumour molecular genetics and pathobiology. By exploiting a wide range of different mechanisms, ncRNAs control fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis: these data have also confirmed their role as oncogenes or tumor suppressors in cancer development and progression. The existence of a sophisticated RNA-based regulatory system, which dictates the correct functioning of protein-coding networks, has relevant biological and biomedical consequences. Different miRNAs involved in neoplastic and degenerative diseases exhibit potential predictive and prognostic properties. Furthermore, the key roles of ncRNAs make them very attractive targets for innovative therapeutic approaches. Several recent reports have shown that ncRNAs can be secreted by cells into the extracellular environment (i.e., blood and other body fluids): this suggests the existence of extracellular signalling mechanisms, which may be exploited by cells in physiology and pathology. In this review, we will summarize the most relevant issues on the involvement of cellular and extracellular ncRNAs in disease. We will then specifically describe their involvement in CRC pathobiology and their translational applications to CRC diagnosis, prognosis and therapy.

Keywords: Colorectal cancer, MicroRNA, Long non-coding RNAs, Circular RNAs, Diagnosis, Prognosis, Therapy

Core tip: For many decades the predominant view of molecular functioning of organisms stated that proteins represent the main regulators of genomes and their dysfunctions were the first cause of diseases. This protein-centred view was too simplistic to explain the complexity of cancer. In the last few years many studies have revealed that about 85% of our genome is pervasively transcribed, mainly as non-protein-coding RNAs (ncRNAs). The discovery of countless molecular alterations of ncRNAs related to cancer changed the paradigms of cancer biology. In this review, we report recent advances in the discovery of ncRNAs involved in Colorectal Cancer pathobiologies, and their potential applications in diagnosis, prognosis and therapy.