Mechanistic Roles of Noncoding RNAs in Lung Cancer Biology and Their Clinical Implications

Abstract

Lung cancer biology has traditionally focused on genomic and epigenomic deregulation of protein-coding genes to identify oncogenes and tumor suppressors diagnostic and therapeutic targets. Another important layer of cancer biology has emerged in the form of noncoding RNAs (ncRNAs), which are major regulators of key cellular processes such as proliferation, RNA splicing, gene regulation, and apoptosis. In the past decade, microRNAs (miRNAs) have moved to the forefront of ncRNA cancer research, while the role of long noncoding RNAs (lncRNAs) is emerging. Here we review the mechanisms by which miRNAs and lncRNAs are deregulated in lung cancer, the technologies that can be applied to detect such alterations, and the clinical potential of these RNA species. An improved comprehension of lung cancer biology will come through the understanding of the interplay between deregulation of non-coding RNAs, the protein-coding genes they regulate, and how these interactions influence cellular networks and signalling pathways.

Figure 1

Schematic depiction of ncRNA deregulation and its impact on regulatory proteins. (a) (i) normal levels of EZH2 are maintained by a balance of EZH2 transcription and miR-101 regulation. (ii) EZH2 is overexpressed as a result of copy number gain of the EZH2 locus. (iii) EZH2 is overexpressed as a result of miR-101 loss. (b) hypothetical scenario of crizotinib resistance. miR-628 is overexpressed resulting in increased degradation of putative target transcript, CASP3, required for crizotinib-induced cell death. (c) (i) normal levels of PTEN are maintained through the ability of its pseudogene, PTENP1, to act as a miRNA sponge. (ii) mutation in the 3′-UTR of PTENP1 results in loss of miRNA binding and redirection of the miRNA to degrade PTEN.