Increasing matrix stiffness upregulates vascular endothelial growth factor expression in hepatocellular carcinoma cells mediated by integrin β1.
Matrix stiffness as a novel regulation factor involves in modulating the pathogenesis of hepatocellular carcinoma (HCC) invasion or metastasis. However, the mechanism by which matrix stiffness modulates HCC angiogenesis remains unknown. Here, using buffalo rat HCC models with different liver matrix stiffness backgrounds and an in vitro cell culture system of mechanically tunable Collagen1 (COL1)-coated polyacrylamide gel, we investigated the effects of different matrix stiffness levels on vascular endothelial growth factor (VEGF) expression in HCC cells and explored its regulatory mechanism for controlling HCC angiogenesis. Tissue microarray analysis showed that the expression levels of VEGF and CD31 were gradually upregulated in tumor tissues with increasing COL1 and lysyl oxidase (LOX) expression, indicating a positive correlation between tumor angiogenesis and matrix rigidity. The expression of VEGF and the phosphorylation levels of PI3K and Akt were all upregulated in HCC cells on high-stiffness gel than on low-stiffness gel. Meanwhile, alteration of intergrin β1 expression was found to be the most distinctive, implying that it might mediate the response of HCC cells to matrix stiffness simulation. After integrin β1 was blocked in HCC cells using specific monoclonal antibody, the expression of VEGF and the phosphorylation levels of PI3K and Akt at different culture times were accordingly suppressed and downregulated in the treatment group as compared with those in the control group. All data suggested that the extracellular matrix stiffness stimulation signal was transduced into HCC cells via integrin β1, and this signal activated the PI3K/Akt pathway and upregulated VEGF expression. This study unveils a new paradigm in which matrix stiffness as initiators to modulate HCC angiogenesis.
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Yinying
Y
Dong
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Xiaoying
X
Xie
Department of Oncology, Zhongshan Hospital Subdivision, Fudan University, Shanghai 200052, PR China.
Zhiming
Z
Wang
Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, PR China.
Chao
C
Hu
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Qiongdan
Q
Zheng
Department of Radiology, Shanghai Cancer Center, Fudan University, Shanghai 200032, PR China.
Yaohui
Y
Wang
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Rongxin
R
Chen
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Tongchun
T
Xue
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Jie
J
Chen
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Dongmei
D
Gao
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Weizhong
W
Wu
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China.
Zhenggang
Z
Ren
Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Xue Yuan Road, Shanghai 200032, PR China. Electronic address: cui.jiefeng@zs-hospital.sh.cn.
Jiefeng
J
Cui
D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D019012:Integrin beta1 / Q000502:physiology*; D008084:Lipoxygenase / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011915:Rats, Inbred BUF; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D024042:Collagen Type I; D019012:Integrin beta1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D008084:Lipoxygenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Hepatocellular carcinoma; Integrin β1; Matrix stiffness; Vascular endothelial growth factor