Noncoding RNAs and Liquid Biopsy in Lung Cancer: A Literature Review

Abstract

Lung cancer represents a genetically heterogeneous disease with low survival rates. Recent data have evidenced key roles of noncoding RNAs in lung cancer initiation and progression. These functional RNA molecules that can act as both oncogenes and tumor suppressors may become future biomarkers and more efficient therapeutic targets. In the precision medicine era, circulating nucleic acids have the potential to reshape the management and prognosis of cancer patients. Detecting genomic alterations and level variations of circulating nucleic acids in liquid biopsy samples represents a noninvasive method for portraying tumor burden. Research is currently trying to validate the potential role of liquid biopsy in lung cancer screening, prognosis, monitoring of disease progression, and treatment response. However, this method requires complex detection assays, and implementation of plasma genotyping in clinical practice continues to be hindered by discrepancies that arise when compared to tissue genotyping. Understanding the genomic landscape of lung cancer is essential in order to provide useful and innovative research in the age of patient-tailored therapy. In this landscape, the noncoding RNAs play a crucial role due to their target genes that dramatically influence the tumor microenvironment and the response to therapy. This article addresses present and future possible roles of liquid biopsy in lung cancer. It also discusses how the complex role of noncoding RNAs in lung tumorigenesis could influence the management of this pathology.

Keywords: liquid biopsy; lung cancer; noncoding RNA.

Figure 1

Main long noncoding RNAs (lncRNAs) related to the diagnosis and prognosis of non-small-cell lung cancer (NSCLC).

Figure 2

Canonical miRNA genesis and processing pathway. The miRNA gene is transcribed in the nucleus from intronic, intergenic, or polycistronic loci by RNA polymerase II or III and forms a transcript that is called primary miRNA (pri-miRNA). pri-miRNA hairpins are double-stranded RNA (dsRNA) structures cleaved by Drosha, an RNAse III-type enzyme, and Pasha, also known as DiGeorge syndrome critical region gene 8 (DGCR8), to form a 70–100 nucleotide long precursor (pre-miRNA). Pre-miRNA hairpin is transported to cytoplasm by the exportin-5 and RanGTP cofactor and then processed by the Dicer complex, another RNase III enzyme, into a miRNA:miRNA duplex. The unwinding of the duplex forms the 18–23 nt mature miRNA. One strand of the duplex binds to Ago and forms RNA-induced silencing complex (RISC). Once loaded, the RISC can target and induce mRNA negative expression by cleavage, translational inhibition or destabilization and degradation.

Figure 3

The origin of circulating tumor-derived cell-free nucleic acids—mutant DNA and RNA, which includes mRNA and noncoding RNA. cfDNA originates from different forms and levels of apoptosis or necrosis of healthy or diseased tissue or from extracellular vesicles (EVs) secreted by tumor cells. The genetic alterations detected in blood include point mutations, structural rearrangements, copy number alterations, and microsatellite alterations, and methylation of DNA/RNA.