MicroRNA-Based Prophylaxis in a Mouse Model of Cirrhosis and Liver Cancer

• Published in: Molecular therapy. Nucleic acids Vol. 14; pp. 239 - 250
• Main Authors: Callegari, Elisa, Domenicali, Marco, Shankaraiah, Ram Charan, D’Abundo, Lucilla, Guerriero, Paola, Giannone, Ferdinando, Baldassarre, Maurizio, Bassi, Cristian, Elamin, Bahaeldin K., Zagatti, Barbara, Ferracin, Manuela, Fornari, Francesca, Altavilla, Giuseppe, Blandamura, Stella, Silini, Enrico Maria, Gramantieri, Laura, Sabbioni, Silvia, Negrini, Massimo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019; Elsevier Limited; American Society of Gene & Cell Therapy; Elsevier
• Subjects: Animals; Carbon tetrachloride; CCl4; Cirrhosis; Cyclin-dependent kinases; Fibrosis; Gene expression; Growth factors; HCC; Hepatocellular carcinoma; Hepatotoxicity; Kinases; Liver cancer; Liver cirrhosis; Liver diseases; MicroRNAs; miRNA; Nodules; Oligonucleotides; Phenotypes; Phosphatase; Prophylaxis; Proteins; Rodents; Software; transgenic animals; Transgenic mice; Tumors; Ultrasonic imaging; United States > US; microRNAs; transgenic animals; CCl4; HCC; carbon tetrachloride; prophylaxis; hepatocellular carcinoma; cirrhosis; CCl
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2018.11.018

Most hepatocellular carcinomas (HCCs) arise in the context of chronic liver disease and/or cirrhosis. Thus, chemoprevention in individuals at risk represents an important but yet unproven approach. In this study, we investigated the ability of microRNA (miRNA)-based molecules to prevent liver cancer development in a cirrhotic model. To this end, we developed a mouse model able to recapitulate the natural progression from fibrosis to HCC, and then we tested the prophylactic activity of an miRNA-based approach in the model. The experiments were carried out in the TG221 transgenic mouse, characterized by the overexpression of miR-221 in the liver and predisposed to the development of liver tumors. TG221 as well as wild-type mice were exposed to the hepatotoxin carbon tetrachloride (CCl4) to induce chronic liver damage. All mice developed liver cirrhosis, but only TG221 mice developed nodular lesions in 100% of cases within 6 months of age. The spectrum of lesions ranged from dysplastic foci to carcinomas. To investigate miRNA-based prophylactic approaches, anti-miR-221 oligonucleotides or miR-199a-3p mimics were administered to TG221 CCl4-treated mice. Compared to control animals, a significant reduction in number, size, and, most significantly, malignant phenotype of liver nodules was observed, thus demonstrating an important prophylactic action of miRNA-based molecules. In summary, in this article, we not only report a simple model of liver cancer in a cirrhotic background but also provide evidence for a potential miRNA-based approach to reduce the risk of HCC development.