The roles and mechanisms of miRNA in HBV-HCC carcinogenesis: Why no therapeutic agents after 30 years?

Hepatitis B-associated hepatocellular carcinoma (HBV-HCC) remains an intractable high-mortality solid tumor cancer that accounted for 42% of global HCC cases in 2019. Despite some developments in systemic therapy, only a small subset of late-stage HCC patients responds positively to recently developed therapeutic innovations. MicroRNAs (miRNAs) act as an ancillary epigenetic system that can regulate genome expression in all cancer pathways including HCC. The molecular mechanisms of miRNA regulation in cancer pathogenesis offered researchers a new approach that was widely hoped would translate into miRNA-based drugs and diagnostics. Thirty years on, miRNA-based diagnostic and therapeutic agents for HCC remain a work-in-progress (WIP) and no current miRNA HCC clinical trial has progressed to Phase 4. The question remains why this is the case after 30 years and what is the way forward. The major findings and contribution of this paper are that it illustrates the complexity of the HBV-miRNA interactome in HBV-HCC in all cellular processes, as well as the ancillary role of miRNA in the epigenetic and immune systems. This is combined with a review of the outcomes and problems of clinical trials, to explain why miRNA therapeutics and diagnostics have not progressed to approved drugs or serum-based diagnostic tests. The way forward suggests a radical rethink might be so that involves the incorporation of AI, bioinformatics, and nanotechnology to solve the problem. [ABSTRACT FROM AUTHOR]