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Fluid shear stress activates YAP to promote epithelial-mesenchymal transition in hepatocellular carcinoma.

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机构： [1]Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China. [2]National Engineering Research Center for Biomaterials, Chengdu, China. [3]West China Hospital, Sichuan University, Chengdu, China. [4]Department of Physiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China. [5]National Clinical Research Center for Child Health, Zhejiang University, Hangzhou, China. [6]Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.

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关键词： epithelial–mesenchymal transition fluid shear stress yes-associated protein

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Epithelial-mesenchymal transition (EMT) mediated by fluid shear stress (FSS) in the tumor microenvironment plays an important role in driving metastasis of the malignant tumor. As a mechanotransducer, Yes-associated protein (YAP) is known to translocate into the nucleus to initiate transcription of genes involved in cell proliferation upon extracellular biophysical stimuli. Here, we showed that FSS facilitated cytoskeleton rearrangement in hepatocellular carcinoma cells, which led to the release of YAP from its binding partner, integrin β subunit, in the cytomembrane. Moreover, we found that upregulation of guanine nucleotide exchange factor (GEF)-H1, a microtubule-associated Rho GEF, is a critical step in the FSS-induced translocation of YAP. Nuclear YAP activated the expression of the EMT-regulating transcription factor SNAI1, but suppressed the expression of N6-methyladenosine (m6 A) modulators; together, this promoted the expression of EMT-related genes. We also observed that FSS-treated HepG2 cells showed markedly increased tumorigenesis and metastasis in vivo. Collectively, our findings unravel the underlying molecular processes by which FSS induces translocation of YAP from the cytomembrane to the nucleus, contributes to EMT and enhances metastasis in hepatocellular carcinoma.© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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出版当年[2021]版：

大类 | 2 区医学

小类 | 2 区肿瘤学

最新[2023]版：

大类 | 2 区

医学

小类 | 2 区肿瘤学

第一作者：

第一作者机构： [1]Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China. [2]National Engineering Research Center for Biomaterials, Chengdu, China.

通讯作者：

通讯机构： [1]Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China. [*1]Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China

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