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microRNA-25 通过调控泛素连接酶 Fbxw7 在肝癌中发挥致癌作用。

MicroRNA-25 Exerts an Oncogenic Function by Regulating the Ubiquitin Ligase Fbxw7 in Hepatocellular Carcinoma.

机构信息

Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto City, Kumamoto, Japan.

Department of Chemistry, Helwan University, Cairo, Egypt.

出版信息

Ann Surg Oncol. 2021 Nov;28(12):7973-7982. doi: 10.1245/s10434-021-09778-2. Epub 2021 Apr 22.

Abstract

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.

摘要

背景

微小 RNA(miRNA)表达异常与肿瘤进展有关。先前的报告表明,微小 RNA-25(miR-25)在多种癌症中作为肿瘤抑制因子或癌基因发挥作用。然而,其在肝细胞癌(HCC)中的分子机制尚不清楚。F-box 和 WD 重复结构域 7(Fbxw7)是一种重要的肿瘤抑制因子,是癌症中泛素-蛋白酶体系统最重要的失调蛋白之一。我们的目的是阐明 miR-25 和 Fbxw7 在 HCC 中的作用,并阐明 Fbxw7 调节的机制。

方法

通过免疫组织化学法检测 210 例固定石蜡包埋 HCC 样本中的 Fbxw7 表达,通过实时定量 PCR 法检测 142 例冷冻 HCC 组织样本中的 miR-25 表达。在体外测定 miR-25 的致癌功能及其对 Fbxw7 表达的调控作用。

结果

miR-25 在 HCC 组织中表达高于相邻正常组织,与预后不良显著相关。此外,它与 HCC 组织中 Fbxw7 的表达呈负相关。此外,miR-25 抑制显著降低了 HCC 细胞在体外的增殖、迁移和侵袭。

结论

miR-25 可能通过抑制 Fbxw7 促进 HCC 患者的肿瘤进展,可作为 HCC 治疗的有前途的分子靶点。

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