Abstract
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.
Highlights
Hepatocellular carcinoma (HCC), the major form of primary liver tumors, is one of the most common cancers worldwide
In order to explore a possible relationship between miR-122 and SerpinB3, we performed a computational analysis that identified SerpinB3 as a miR-122 hypothetical target gene (TargetScan algorithm Figure 1A)
Transfection with miR-122 mimics a decrease of SerpinB3 mRNA levels was observed, whereas transfection with anti-miR-122 oligonucleotides determined an increase of SerpinB3 levels
Summary
Hepatocellular carcinoma (HCC), the major form of primary liver tumors, is one of the most common cancers worldwide. New advances in genomics provide an increasingly comprehensive understanding of HCC development, the molecular pathogenesis of HCC remains poorly understood, and the clinical heterogeneity of HCC together with the lack of diagnostic biomarkers and treatment strategies contribute to the high mortality rate recorded for this aggressive tumor [3]. For these reasons, research and development for new effective targeted therapies still represent a major clinical need. They are involved in various biological and pathological processes and their deregulation has been often associated with disease progression and cancer [5,6]
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