Although previous evidence indicates close involvement of CD147 in the pathogenesis of liver fibrosis, the underlying molecular mechanisms and its therapeutic value remain largely unknown. In the present study, we investigated the biological roles of CD147 in liver fibrosis and assessed its therapeutic value as a target molecule in the CCl4-induced liver fibrosis mouse model. We found that CD147 was highly expressed in both hepatocytes and SECs (sinusoidal endothelial cells) in fibrotic liver tissues. Additionally, it was significantly associated with the fibrosis stage. TGF-β1 (transforming growth factor β1) was found to be mainly responsible for the up-regulation of CD147. Bioinformatic and experimental data suggest a functional link between CD147 expression and VEGF-A (vascular endothelial growth factor A)/VEGR-2 (VEGF receptor 2) signalling-mediated angiogenesis in fibrotic liver tissues. Furthermore, we observed that the CD147-induced activation of the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway promotes the production of VEGF-A in hepatocytes and expression of VEGFR-2 in SECs, which was found to enhance the angiogenic capability of SECs. Finally, our data indicate that blocking of CD147 using an mAb (monoclonal antibody) attenuated liver fibrosis progression via inhibition of VEGF-A/VEGFR-2 signalling and subsequent amelioration of microvascular abnormality in the CCl4-induced mouse model. Our findings suggest a novel functional mechanism that CD147 may promote liver fibrosis progression via inducing the VEGF-A/VEGFR-2 signalling pathway-mediated cross-talk between hepatocytes and SECs. New strategies based on the intervention of CD147 can be expected for prevention of liver fibrosis.
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Research Article|
July 22 2015
CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells
Zhaoyong Yan;
Zhaoyong Yan
1
*Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
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Kai Qu;
Kai Qu
1
†Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, China
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Jing Zhang;
Jing Zhang
1
‡State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China
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Qichao Huang;
Qichao Huang
‡State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China
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Ping Qu;
Ping Qu
‡State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China
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Xinsen Xu;
Xinsen Xu
†Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, China
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Peng Yuan;
Peng Yuan
*Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
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Xiaojun Huang;
Xiaojun Huang
‡State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China
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Yongping Shao;
Yongping Shao
§Center for Translational Medicine, Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China
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Chang Liu;
Chang Liu
†Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, China
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Hongxin Zhang;
*Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
Correspondence: Dr Jinliang Xing (email [email protected]) or Dr Hongxin Zhang (email [email protected]).
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Jinliang Xing
‡State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China
Correspondence: Dr Jinliang Xing (email [email protected]) or Dr Hongxin Zhang (email [email protected]).
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Publisher: Portland Press Ltd
Received:
December 15 2014
Revision Received:
April 15 2015
Accepted:
June 16 2015
Accepted Manuscript online:
June 16 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2015 Authors; published by Portland Press Limited
2015
Clin Sci (Lond) (2015) 129 (8): 699–710.
Article history
Received:
December 15 2014
Revision Received:
April 15 2015
Accepted:
June 16 2015
Accepted Manuscript online:
June 16 2015
Citation
Zhaoyong Yan, Kai Qu, Jing Zhang, Qichao Huang, Ping Qu, Xinsen Xu, Peng Yuan, Xiaojun Huang, Yongping Shao, Chang Liu, Hongxin Zhang, Jinliang Xing; CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells. Clin Sci (Lond) 1 October 2015; 129 (8): 699–710. doi: https://doi.org/10.1042/CS20140823
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