Cirrhotic stiffness affects the migration of hepatocellular carcinoma cells and induces sorafenib resistance through YAP
Cirrhotic stiffness affects the migration of hepatocellular carcinoma cells and induces sorafenib resistance through YAP
复制标题
肝硬化僵硬影响肝癌细胞迁移并通过YAP诱导索拉非尼耐药
DOI：
10.1002/jcp.27078
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发表时间：
2019-03-01
影响因子：
5.6
通讯作者：
Wu, Congying
中科院分区：
文献类型：
--
作者：
Gao, Jian;Rong, Yingxue;Wu, Congying
大多数肝细胞癌（HCC）联合收割机合并肝硬化。肝硬化与干扰肝癌靶向药物（包括索拉非尼）的作用有关。肿瘤微环境的改变包括生物化学和生物力学因素。在这项研究中，我们诱导肝癌细胞索拉非尼耐药。我们观察到这些索拉非尼耐药细胞的细胞形态、细胞骨架结构和细胞硬度的变化，类似于那些适应更硬基质的细胞。为了研究机械因素在HCC细胞生长和耐药性中的作用，我们使用了具有可调节刚度的体外细胞培养系统，模拟正常或硬化的肝组织。我们发现机械适应赋予肝癌细胞运动性和索拉非尼耐药性增加。我们进一步报道了转录辅激活因子雅普参与的机制。我们的研究结果强调了机械因素在肿瘤细胞与其微环境相互作用中的重要作用。
A majority of hepatocellular carcinomas (HCCs) combine with liver cirrhosis. The cirrhotic liver has been implicated in interfering with the effects of HCC-targeted drugs, including sorafenib. Alterations in the tumor microenvironment of the cirrhotic liver include both biochemical and biomechanical factors. In this study, we induced sorafenib resistance in HCC cells. We observed changes in cell morphology, cytoskeletal architecture, and cellular stiffness in these sorafenib-resistant cells, resembling those adapted to stiffer substrates. To examine the contribution of mechanical factors in HCC cell growth and drug resistance, we used an in vitro cell culture system with adjustable stiffness mimicking the normal or cirrhotic liver tissues. We identified that mechanical adaptation conferred HCC cells with increased motility and sorafenib resistance. We further reported the mechanism underlying the involvement of the transcription coactivator YAP. Our results underline the important role of mechanical factors in the interaction between tumor cells and their microenvironment.