MicroRNA-25 Exerts an Oncogenic Function by Regulating the Ubiquitin Ligase Fbxw7 in Hepatocellular Carcinoma
MicroRNA-25 Exerts an Oncogenic Function by Regulating the Ubiquitin Ligase Fbxw7 in Hepatocellular Carcinoma
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DOI：
10.1245/s10434-021-09778-2
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发表时间：
2021-04-22
影响因子：
3.7
通讯作者：
Baba, Hideo
中科院分区：
文献类型：
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作者：
El-mezayen, Hatem;Yamamura, Kensuke;Baba, Hideo
背景microRNA（miRNA）表达异常与肿瘤进展有关。先前的报道表明microRNA-25（miR-25）在多种癌症中作为肿瘤抑制基因或癌基因。然而，其在肝细胞癌（HCC）中的分子机制仍不清楚。F-box and WD repeat domain 7（Fbxw 7）是一种重要的肿瘤抑制因子，是肿瘤中泛素-蛋白酶体系统中最重要的失调蛋白之一。我们的目的是阐明miR-25和Fbxw 7在HCC中的作用，并阐明Fbxw 7的调控机制。方法采用免疫组化法检测210例固定石蜡包埋的HCC组织中Fbxw 7的表达，采用实时荧光定量PCR法检测142例冰冻HCC组织中miR-25的表达。在体外测定miR-25的致癌功能及其在Fbxw 7表达调节中的作用。结果miR-25在肝癌组织中的表达高于癌旁正常组织，且与患者的预后相关。此外，它与肝癌组织中Fbxw 7的表达呈负相关。此外，miR-25抑制显著降低了体外HCC细胞的增殖、迁移和侵袭。结论miR-25可能通过抑制Fbxw 7的表达促进肝癌的进展，有望成为肝癌治疗的分子靶点。
Background MicroRNA (miRNA) expression abnormalities are implicated in tumor progression. Previous reports have indicated that microRNA-25 (miR-25) acts as a tumor suppressor or oncogene in diverse cancers. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are still unclear. F-box and WD repeat domain 7 (Fbxw7) is a critical tumor suppressor and is one of the most important deregulated proteins of the ubiquitin-proteasome system in cancer. Our objective was to elucidate the role of miR-25 and Fbxw7 in HCC and to clarify the mechanism by which Fbxw7 is regulated. Methods Fbxw7 expression was estimated in 210 fixed paraffin-embedded HCC samples by immunohistochemistry, and miR-25 expression was evaluated in 142 frozen HCC tissue samples by quantitative real-time PCR. Oncogenic functions of miR-25 and its role in the regulation of Fbxw7 expression were assayed in vitro. Results miR-25 was overexpressed in HCC tissue compared with adjacent normal tissue and significantly correlated with a poorer prognosis. Moreover, it was inversely correlated with Fbxw7 expression in HCC tissues. Furthermore, miR-25 inhibition significantly reduced the proliferation, migration, and invasion of HCC cells in vitro. Conclusion miR-25 may promote tumor progression in HCC patients by repression of Fbxw7 and could serve as a promising molecular target for HCC treatment.