Department of Medicine, Columbia University, New York, NY.
Department of Pathology, Tianjin First Center Hospital, Tianjin, China.
Hepatology. 2018 Jun;67(6):2414-2429. doi: 10.1002/hep.29627. Epub 2018 Jan 18.
Fibrosis and cancer represent two major complications of chronic liver disease. MicroRNAs have been implicated in the development of fibrosis and cancer, thus constituting potential therapeutic targets. Here, we investigated the role of microRNA-21 (miR-21), a microRNA that has been implicated in the development of fibrosis in multiple organs and has also been suggested to act as an "oncomir." Accordingly, miR-21 was the microRNA that showed the strongest up-regulation in activated hepatic stellate cells (HSCs) in multiple models of fibrogenesis, with an 8-fold to 24-fold induction compared to quiescent HSCs. However, miR-21 antisense inhibition did not suppress the activation of murine or human HSCs in culture or in liver slices. Moreover, genetic deletion of miR-21 in two independently generated knockout mice or miR-21 antisense inhibition did not alter HSC activation or liver fibrosis in models of toxic and biliary liver injury. Despite a strong up-regulation of miR-21 in injury-associated hepatocellular carcinoma and in cholangiocarcinoma, miR-21 deletion or antisense inhibition did not reduce the development of liver tumors. As inhibition of the most up-regulated microRNA did not affect HSC activation, liver fibrosis, or fibrosis-associated liver cancer, we additionally tested the role of microRNAs in HSCs by HSC-specific Dicer deletion. Although Dicer deletion decreased microRNA expression in HSCs and altered the expression of select genes, it only exerted negligible effects on HSC activation and liver fibrosis.
Genetic and pharmacologic manipulation of miR-21 does not inhibit the development of liver fibrosis and liver cancer. Moreover, suppression of microRNA synthesis does not significantly affect HSC phenotype and activation. (Hepatology 2018;67:2414-2429).
纤维化和癌症是慢性肝病的两种主要并发症。microRNAs 参与纤维化和癌症的发展，因此构成潜在的治疗靶点。在这里，我们研究了 microRNA-21（miR-21）的作用，miR-21 是一种在多个器官纤维化发展中被牵连的 microRNA，也被认为是一种“癌基因”。因此，miR-21 是在多种纤维化模型中活化的肝星状细胞（HSCs）中表现出最强上调的 microRNA，与静息 HSCs 相比，诱导倍数为 8 至 24 倍。然而，miR-21 反义抑制在培养物或肝切片中并未抑制鼠或人 HSCs 的活化。此外，在两种独立产生的敲除小鼠或 miR-21 反义抑制中遗传缺失 miR-21 并没有改变毒性和胆汁性肝损伤模型中的 HSC 活化或肝纤维化。尽管 miR-21 在与损伤相关的肝细胞癌和胆管癌中强烈上调，但 miR-21 缺失或反义抑制并未减少肝肿瘤的发展。由于抑制最上调的 microRNA 并未影响 HSC 活化、肝纤维化或纤维化相关的肝癌，我们还通过 HSC 特异性 Dicer 缺失测试了 microRNAs 在 HSCs 中的作用。尽管 Dicer 缺失降低了 HSCs 中的 microRNA 表达并改变了一些基因的表达，但它仅对 HSC 活化和肝纤维化产生微小影响。
miR-21 的遗传和药理学操作并不能抑制肝纤维化和肝癌的发展。此外，抑制 microRNA 合成并不会显著影响 HSC 表型和活化。（Hepatology 2018;67:2414-2429）。
