MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside

Abstract

Non-coding RNAs represent a significant proportion of the human genome. After having been considered as 'junk' for a long time, non-coding RNAs are now well established as playing important roles in maintaining cellular homeostasis and functions. Some non-coding RNAs show cell- and tissue-specific expression patterns and are specifically deregulated under pathological conditions (e.g. cancer). Therefore, non-coding RNAs have been extensively studied as potential biomarkers in the context of different diseases with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) for several years. Since their discovery, miRNAs have attracted more attention than lncRNAs in research studies; however, both families of non-coding RNAs have been established to play an important role in gene expression control, either as transcriptional or post-transcriptional regulators. Both miRNAs and lncRNAs can regulate key genes involved in the development of cancer, thus influencing tumour growth, invasion, and metastasis by increasing the activation of oncogenic pathways and limiting the expression of tumour suppressors. Furthermore, miRNAs and lncRNAs are also emerging as important mediators in drug-sensitivity and drug-resistance mechanisms. In the light of these premises, a number of pre-clinical and early clinical studies are exploring the potential of non-coding RNAs as new therapeutics. The aim of this review is to summarise the latest knowledge of the use of miRNAs and lncRNAs as therapeutic tools for cancer treatment.

Fig. 1

Illustration of the multi-step microRNA (miRNA) biogenesis pathways, miRNA-target messenger RNA (mRNA) interaction and the exosome-mediated miRNA secretion pathway along with relative druggable concentrations. Black arrows refer to enzymatic steps, blue arrows refer to therapeutic approaches enhancing miRNA expression, while red lines refer to therapeutic approaches blocking miRNA functions. For details see the main text

Fig. 2

Illustration of the possibilities to target and alter the expression level of long non-coding RNAs (lncRNAs). a Nuclear localised lncRNAs can be targeted by chemically modified antisense oligonucleotides (ASOs) resulting in RNAseH-dependent degradation. b Antisense oligonucleotides or small-molecule inhibitors can be used to inhibit the lncRNA-RNA-binding protein interactions. c Long non-coding RNA expression can be modulated via steric blocking of the promoter or by using genome-editing techniques such as CRISPR/Cas9 [–184]. d Up-regulation of lncRNA expression can be mediated by knock-down of the relevant corresponding natural antisense transcripts (NATs). e Long non-coding RNAs present in the cytoplasm can be degraded with small interfering RNA (siRNA)-based strategies involving the multiprotein complex RISC, RNAse dicer and endonuclease Argonaut2-dependent degradation pathway