Cirrhotic stiffness affects the migration of hepatocellular carcinoma cells and induces sorafenib resistance through YAP

被引:37
作者
Gao, Jian [1 ]
Rong, Yingxue [1 ]
Huang, Yuxing [1 ]
Shi, Peng [1 ]
Wang, Xitao [2 ]
Meng, Xuan [3 ,4 ]
Dong, Jiahong [5 ]
Wu, Congying [1 ]
机构
[1] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Inst Syst Biomed, 38 Xueyuan Rd, Beijing 100191, Peoples R China
[2] Cent S Univ, Xiangya Hosp, Dept Pancreaticobiliary Surg, Changsha, Hunan, Peoples R China
[3] Chinese Peoples Liberat Army Gen Hosp, Hosp & Inst Hepatobiliary Surg, Beijing, Peoples R China
[4] Xuzhou Med Coll, Jiangsu Ctr Collaborat & Innovat Canc Biotherapy, Inst Canc, Xuzhou, Jiangsu, Peoples R China
[5] Beijing Tsinghua Changgung Hosp, Dept Hepatobiliary Surg, Beijing, Peoples R China
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
drug resistance; hepatocellular carcinoma (HCC); sorafenib; tumor biomechanics; tumor cell migration; YAP; ACTIN DYNAMICS; DOUBLE-BLIND; YAP/TAZ; FORCE; MICROENVIRONMENT; MECHANISMS; LAPATINIB; INVASION; PHASE-3; GROWTH;
D O I
10.1002/jcp.27078
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:2639 / 2648
页数:10
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