RNA renaissance: Harnessing non-coding RNA therapeutics for hepatocellular carcinoma

Non-coding RNAs (ncRNAs) represent a diverse group of RNAs that exhibit an important role in various cellular mechanisms by regulating gene expression at both transcription and translation levels without being translated into proteins. Despite their canonical cellular functions, dysregulation of ncRNAs especially microRNAs (miRNAs), circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) have been widely documented in various diseases including cancer. Owing to their potential to regulate multiple genes and signaling pathways simultaneously, targeting individual ncRNA provides a multi-faceted therapeutic approach. Moreover, the liver's inherent ability for rapid uptake of systemically administered such ncRNAs-based therapy renders it as a suitable target for developing effective therapeutics for liver cancer. Here, we have conducted a meta-analysis of the published literature on miRNAs deregulated in HCC to uncover multifunctional miRNAs driving various oncogenic pathways corroborated by experimental validations as well. However, for therapeutic purposes, lncRNAs that sequester several such miRNAs have been also identified in HCC, highlighting them as promising targets for ncRNA-based therapy in HCC. Regardless of promising preclinical studies, very few ncRNA-based therapeutics have entered clinical trials. Therefore, recognizing these limitations, we have discussed the challenges impeding the development of ncRNA-based treatments along with some probable solutions.