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

1
Venetian Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy
2
Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
3
Department of Medicine, University of Padua, 35128 Padua, Italy
4
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; https://doi.org/10.3390/jcm8020171
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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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. 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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