Higher Matrix Stiffness Upregulates Osteopontin Expression in Hepatocellular Carcinoma Cells Mediated by Integrin β1/GSK3β/β-Catenin Signaling Pathway.
Increased stromal stiffness is associated with hepatocellular carcinoma (HCC) development and progression. However, the molecular mechanism by which matrix stiffness stimuli modulate HCC progress is largely unknown. In this study, we explored whether matrix stiffness-mediated effects on osteopontin (OPN) expression occur in HCC cells. We used a previously reported in vitro culture system with tunable matrix stiffness and found that OPN expression was remarkably upregulated in HCC cells with increasing matrix stiffness. Furthermore, the phosphorylation level of GSK3β and the expression of nuclear β-catenin were also elevated, indicating that GSK3β/β-catenin pathway might be involved in OPN regulation. Knock-down analysis of integrin β1 showed that OPN expression and p-GSK3β level were downregulated in HCC cells grown on high stiffness substrate compared with controls. Simultaneously, inhibition of GSK-3β led to accumulation of β-catenin in the cytoplasm and its enhanced nuclear translocation, further triggered the rescue of OPN expression, suggesting that the integrin β1/GSK-3β/β-catenin pathway is specifically activated for matrix stiffness-mediated OPN upregulation in HCC cells. Tissue microarray analysis confirmed that OPN expression was positively correlated with the expression of LOX and COL1. Taken together, high matrix stiffness upregulated OPN expression in HCC cells via the integrin β1/GSK-3β/β-catenin signaling pathway. It highlights a new insight into a pathway involving physical mechanical signal and biochemical signal molecules which contributes to OPN expression in HCC cells.
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.
Yang
Y
You
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
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
Department of Interventional 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.
Lan
L
Zhang
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.
Xiaoying
X
Xie
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
Chao
C
Hu
Department of Oncology, Zhongshan Hospital Subdivision, Fudan University, Shanghai, 200052, PR China.
Zhiming
Z
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.
Yanhong
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.
Jiefeng
J
Cui
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
D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D046888:Tissue Array Analysis; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
D019012:Integrin beta1; C506895:SPP1 protein, human; D051176:beta Catenin; D053495:Osteopontin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3