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MiR-122 Targets SerpinB3 and Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Venetian Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy
Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
Department of Medicine, University of Padua, 35128 Padua, Italy
Department of Surgical, Gastroenterological and Oncological Sciences, University of Padua, 35128 Padua, Italy
Author to whom correspondence should be addressed.
The authors contributed equally to the present study.
J. Clin. Med. 2019, 8(2), 171;
Received: 17 December 2018 / Revised: 11 January 2019 / Accepted: 29 January 2019 / Published: 1 February 2019
(This article belongs to the Section Gastroenterology & Hepato-Pancreato-Biliary Medicine)
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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. View Full-Text
Keywords: hepatocellular carcinoma; micro RNA; molecular targets hepatocellular carcinoma; micro RNA; molecular targets

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Turato, C.; Fornari, F.; Pollutri, D.; Fassan, M.; Quarta, S.; Villano, G.; Ruvoletto, M.; Bolondi, L.; Gramantieri, L.; Pontisso, P. MiR-122 Targets SerpinB3 and Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma. J. Clin. Med. 2019, 8, 171.

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