The only first-line treatment approved for advanced hepatocellular carcinoma (HCC) is sorafenib. Since many patients experience drug resistance, the discovery of more effective therapeutic strategies represents an unmet clinical need. MicroRNA (MiR)-122 is downregulated in most HCCs, while oncogenic SerpinB3 is upregulated. Here, we assessed the relationship between miR-122 and SerpinB3 and their influence on cell phenotype and sorafenib resistance in HCC. A bioinformatics analysis identified SerpinB3 among hypothetical miR-122 targets. In SerpinB3-overexpressing HepG2 cells, miR-122 transfection decreased SerpinB3 mRNA and protein levels, whereas miR-122 inhibition increased SerpinB3 expression. Luciferase assay demonstrated the interaction between miR-122 and SerpinB3 mRNA. In an HCC rat model, high miR-122 levels were associated with negative SerpinB3 expression, while low miR-122 levels correlated with SerpinB3 positivity. A negative correlation between miR-122 and SerpinB3 or stem cell markers was found in HCC patients. Anti-miR-122 transfection increased cell viability in sorafenib-treated Huh-7 cells, while miR-122 overexpression increased sorafenib sensitivity in treated cells, but not in those overexpressing SerpinB3. In conclusion, we demonstrated that miR-122 targets SerpinB3, and its low levels are associated with SerpinB3 positivity and a stem-like phenotype in HCC. MiR-122 replacement therapy in combination with sorafenib deserves attention as a possible therapeutic strategy in SerpinB3-negative HCCs.

The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the “personalized-medicine” era.