Inhibition of matrix stiffness relating integrin β1 signaling pathway inhibits tumor growth in vitro and in hepatocellular cancer xenografts

被引:19
|
作者
Wang, Changsong [1 ,2 ]
Jiang, Xiaozhong [1 ,2 ]
Huang, Bin [1 ,2 ]
Zhou, Wenhao [1 ,2 ]
Cui, Xiao [1 ,2 ]
Zheng, Chenghong [1 ,2 ]
Liu, Fenghao [1 ,2 ]
Bi, Jieling [1 ,2 ]
Zhang, Yi [1 ,2 ]
Luo, Hong [1 ,2 ]
Yuan, Lin [1 ,2 ]
Yang, Jianyong [1 ,2 ]
Yu, Yu [1 ,2 ]
机构
[1] Second Peoples Hosp Yibin, Dept Hepatopancreatobiliary Surg, Yibin 644000, Sichuan, Peoples R China
[2] Second Peoples Hosp Yibin, Ctr Diag & Treatment Digest Dis, Yibin 644000, Sichuan, Peoples R China
关键词
Matrix stiffness; Integrin beta 1; ERK1/2; Hepatocellular cancer; CELL; MECHANOTRANSDUCTION; MIGRATION; EMT;
D O I
10.1186/s12885-021-08982-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Cancer development is strictly correlated to composition and physical properties of the extracellular matrix. Particularly, a higher matrix stiffness has been demonstrated to promote tumor sustained growth. Our purpose was to explore the role of matrix stiffness in liver cancer development. Methods: The matrix stiffness of tumor tissues was determined by atomic force microscopy (AFM) analysis. In vitro, we used a tunable Polyacrylamide (PA) hydrogels culture system for liver cancer cells culture. The expression level of integrin beta 1, phosphorylated FAK, ERK1/2, and NF-kappa B in SMMC-7721 cells was measured by western blotting analysis. We performed MTT, colony formation and transwell assay to examine the tumorigenic and metastatic potential of SMMC-7721 cells cultured on the tunable PA hydrogels. SMMC-7721 cancer xenografts were established to explore the anticancer effects of integrin inhibitors. Results: Our study provided evidence that liver tumor tissues from metastatic patients possessed a higher matrix stiffness, when compared to the non-metastatic group. Liver cancer cells cultured on high stiffness PA hydrogels displayed enhanced tumorigenic potential and migrative properties. Mechanistically, activation of integrin beta 1/FAK/ERK1/2/NF-kappa B signaling pathway was observed in SMMC-7721 cells cultured on high stiffness PA hydrogels. Inhibition of ERK1/2, FAK, and NF-kappa B signaling suppressed the pro-tumor effects induced by matrix stiffness. Combination of chemotherapy and integrin beta 1 inhibitor suppressed the tumor growth and prolonged survival time in hepatocellular cancer xenografts. Conclusion: A higher matrix stiffness equipped tumor cells with enhanced stemness and proliferative characteristics, which was dependent on the activation of integrin beta 1/FAK/ERK1/2/NF-kappa B signaling pathway. Blockade of integrin signals efficiently improved the outcome of chemotherapy, which described an innovative approach for liver cancer treatment.
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页数:11
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