Inhibition of microRNA-214 ameliorates hepatic fibrosis and tumor incidence in platelet-derived growth factor C transgenic mice.
Inhibition of microRNA-214 ameliorates hepatic fibrosis and tumor incidence in platelet-derived growth factor C transgenic mice.
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DOI：
10.1111/cas.12730
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发表时间：
2015-09
期刊：
影响因子：
5.7
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Okada H;Honda M;Campbell JS;Takegoshi K;Sakai Y;Yamashita T;Shirasaki T;Takabatake R;Nakamura M;Tanaka T;Kaneko S
差异调节的 microRNA (miRNA) 与肝纤维化相关；然而，它们阻止肝纤维化的潜在用途尚未得到充分利用。我们检测了转基因小鼠模型肝脏中 miRNA 的表达，其中血小板源性生长因子 C (PDGF-C) 过度表达 (Pdgf-c Tg)，导致肝纤维化和脂肪变性，并最终发展为肝细胞癌 (HCC)。 miR-214 的强烈诱导与 Pdgf-c Tg 小鼠、致动脉粥样化高脂饮食诱导的 NASH 小鼠以及慢性乙型或丙型肝炎患者的肝脏纤维化相关。使用 Invivofectamine 2.0 通过尾静脉注射锁核酸 (LNA)-antimiR-214，评估肝纤维化程度和肿瘤发生率。与注射生理盐水或 LNA-miR 对照的对照小鼠相比，用 LNA-antimiR-214 治疗的 Pdgf-c Tg 小鼠的纤维化和肿瘤发生率显着降低。在体外，LNA-antimiR-214 显着改善了 Lx-2 细胞中 TGF-β1 诱导的促纤维化基因表达。 MiR-214 靶向 EGFR 信号转导的负调节因子 Mig-6。 Mimic-miR-214 降低 Huh-7 细胞中 Mig-6 的表达，并增加 EGF 介导的 p-EGFR（Y1173 和 Y845）和 p-Met（Tyr1234/1235）的水平。相反，LNA-antimiR-214 抑制这些基因的表达。总之，miR-214 似乎通过调节 EGFR 和 TGF-β 信号通路参与肝纤维化的发展。 LNA-antimiR-214 是预防肝纤维化的潜在疗法。
Differentially regulated microRNA (miRNA) are associated with hepatic fibrosis; however, their potential usefulness for blocking hepatic fibrosis has not been exploited fully. We examined the expression of miRNA in the liver of a transgenic mouse model in which platelet-derived growth factor C (PDGF-C) is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis and steatosis and the eventual development of hepatocellular carcinoma (HCC). Robust induction of miR-214 correlated with fibrogenesis in the liver of Pdgf-c Tg mice, atherogenic high-fat diet-induced NASH mice, and patients with chronic hepatitis B or C. Pdgf-c Tg mice were injected with locked nucleic acid (LNA)-antimiR-214 via the tail vein using Invivofectamine 2.0 and the degree of hepatic fibrosis and tumor incidence were evaluated. Pdgf-c Tg mice treated with LNA-antimiR-214 showed a marked reduction in fibrosis and tumor incidence compared with saline or LNA-miR-control-injected control mice. In vitro, LNA-antimiR-214 significantly ameliorated TGF-β1-induced pro-fibrotic gene expression in Lx-2 cells. MiR-214 targets a negative regulator of EGFR signaling, Mig-6. Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF-mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) in Huh-7 cells. Conversely, LNA-antimiR-214 repressed the expression of these genes. In conclusion, miR-214 appears to participate in the development of hepatic fibrosis by modulating the EGFR and TGF-β signaling pathways. LNA-antimiR-214 is a potential therapy for the prevention of hepatic fibrosis.