Journal of Hepatocellular Carcinoma (May 2021)
MicroRNAs as Modulators of Tumor Metabolism, Microenvironment, and Immune Response in Hepatocellular Carcinoma
Abstract
Laura Gramantieri,1 Catia Giovannini,2,3 Fabio Piscaglia,1,4 Francesca Fornari3,5 1Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 2Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; 3Centre for Applied Biomedical Research - CRBA, University of Bologna, St. Orsola Hospital, Bologna, Italy; 4Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 5Department for Life Quality Studies (QuVi), University of Bologna, Rimini, ItalyCorrespondence: Laura Gramantieri; Francesca FornariUniversity of Bologna, Via Massarenti, 9, Bologna, 40138, ItalyTel/Fax +390512143902Email [email protected]; [email protected]: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers helping patient allocation to the best therapeutic option contribute to poor prognosis in advanced stages. MicroRNAs’ (miRNAs) deregulated expression contributes to tumor development and progression and influences drug resistance in HCC. Accordingly, miRNAs have been extensively investigated as both biomarkers and therapeutic targets. The diagnostic and prognostic roles of circulating miRNAs have been ascertained, though with some inconsistencies across studies. From a therapeutic perspective, miRNA-based approaches demonstrated safety profiles and antitumor efficacy in HCC animal models. Nevertheless, caution should be used when transferring preclinical findings to the clinic, due to possible molecular inconsistency between animal models and the heterogeneous patterns of human diseases. A wealth of information is offered by preclinical studies exploring the mechanisms driving miRNAs’ aberrant expression, the molecular cascades triggered by miRNAs and the corresponding phenotypic changes. Ex-vivo analyses confirmed these results, further shedding light on the intricacy of the human disease often overcoming pre-clinical models. This complexity seems to be ascribed to the intrinsic heterogeneity of HCC, to different risk factors driving its development, as well as to changes across stages and previous treatments. Preliminary findings suggest that miRNAs associated with specific risk factors might be more informative in defined patients’ subgroups. The first issue to be considered when trying to envisage a possible translational perspective is the molecular context that often drives different miRNA functions, as clearly evidenced by “dual” miRNAs. Concerning the possible roles of miRNAs as biomarkers and therapeutic targets, we will focus on miRNAs’ involvement in metabolic pathways and in the modulation of tumor microenvironment, to support their exploitation in defined contexts.Keywords: HCC, microRNA, biomarkers
