Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Prognosis is poor, and therapeutic options are limited. microRNAs (miRNAs) have emerged as potential therapeutic molecules against cancer. Here, we investigated the therapeutic efficacy of miR-199a-3p, a miRNA highly expressed in normal liver and downregulated in virtually all HCCs. The therapeutic value of miR-199a-3p mimic molecules was assayed in the TG221 mouse, a transgenic model highly predisposed to the development of liver cancer. Administration of miR-199a-3p mimics in the TG221 transgenic mouse showing liver cancer led to a significant reduction of number and size of tumor nodules compared to control animals. In vivo delivery confirmed protein downregulation of the miR-199a-3p direct targets, mechanistic target of rapamycin (MTOR) and p21 activated kinase 4 (PAK4), ultimately leading to the repression of FOXM1. Remarkably, the anti-tumor activity of miR-199a-3p mimics was comparable to that obtained with sorafenib. These results suggested that miR-199a-3p may be considered a promising HCC therapeutic option.

肝细胞癌（HCC）是世界范围内与癌症相关的死亡的第二大主要原因。预后差，治疗选择有限。微小RNA（miRNA）已经成为潜在的抗癌治疗分子。在这里，我们研究了miR-199a-3p的治疗功效，miR-199a-3p在正常肝中高表达，而在几乎所有HCC中均下调。在TG221小鼠中测定了miR-199a-3p模拟分子的治疗价值，TG221小鼠是高度易患肝癌的转基因模型。与对照组动物相比，在显示肝癌的TG221转基因小鼠中施用miR-199a-3p模拟物可导致肿瘤结节的数量和大小显着减少。体内传递证实了miR-199a-3p直接靶标，雷帕霉素（MTOR）的机械靶标和p21活化激酶4（PAK4）的蛋白下调，最终导致FOXM1的抑制。值得注意的是，miR-199a-3p模拟物的抗肿瘤活性与索拉非尼所获得的抗肿瘤活性相当。这些结果表明，miR-199a-3p可能被认为是有前途的HCC治疗选择。