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miR-199a-3p modulates MTOR and PAK4 pathways and inhibits tumor growth in a hepatocellular carcinoma transgenic mouse model
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2018-04-12
Elisa Callegari, Lucilla D’Abundo, Paola Guerriero, Carolina Simioni, Bahaeldin K. Elamin, Marta Russo, Alice Cani, Cristian Bassi, Barbara Zagatti, Luciano Giacomelli, Stella Blandamura, Farzaneh Moshiri, Simona Ultimo, Antonio Frassoldati, Giuseppe Altavilla, Laura Gramantieri, Luca Maria Neri, Silvia Sabbioni, Massimo Negrini

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.



中文翻译:

miR-199a-3p在肝细胞癌转基因小鼠模型中调节MTOR和PAK4途径并抑制肿瘤生长

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。

更新日期:2018-04-12
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