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.
MicroRNA-Based Prophylaxis in a Mouse Model of Cirrhosis and Liver Cancer / 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*. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - STAMPA. - 14:(2019), pp. 14.239-14.250. [10.1016/j.omtn.2018.11.018]
MicroRNA-Based Prophylaxis in a Mouse Model of Cirrhosis and Liver Cancer
Domenicali, Marco;Giannone, Ferdinando;Baldassarre, Maurizio;Ferracin, ManuelaFormal Analysis
;Fornari, Francesca;Gramantieri, LauraResources
;
2019
Abstract
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.File | Dimensione | Formato | |
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