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.

大多数肝细胞癌（HCC）是在慢性肝病和/或肝硬化的背景下产生的。因此，对高危个体进行化学预防是一种重要但尚未得到证实的方法。在这项研究中，我们研究了基于 microRNA (miRNA) 的分子在肝硬化模型中预防肝癌发展的能力。为此，我们开发了一种能够重现从纤维化到 HCC 自然进展的小鼠模型，然后我们在该模型中测试了基于 miRNA 的方法的预防活性。该实验是在 TG221 转基因小鼠中进行的，该小鼠的特点是肝脏中 miR-221 过度表达，并且易于发生肝脏肿瘤。TG221 以及野生型小鼠暴露于肝毒素四氯化碳（CCl ₄）以诱导慢性肝损伤。所有小鼠均出现肝硬化，但只有TG221小鼠在6月龄内100%出现结节性病变。病变范围从发育异常灶到癌。为了研究基于 miRNA 的预防方法，将抗 miR-221 寡核苷酸或 miR-199a-3p 模拟物给予 TG221 CCl ₄处理的小鼠。与对照动物相比，观察到肝结节的数量、大小以及最显着的恶性表型显着减少，从而证明基于 miRNA 的分子具有重要的预防作用。总之，在本文中，我们不仅报告了肝硬化背景下肝癌的简单模型，而且还为基于 miRNA 的潜在方法降低 HCC 发展风险提供了证据。