title: CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells.
abstract: 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.
authors.affiliation: Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Qu
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Qu
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Xinsen
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, China xingjl@fmmu.edu.cn Hongxinzhang@fmmu.edu.cn.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China xingjl@fmmu.edu.cn Hongxinzhang@fmmu.edu.cn.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
mesh_terms: D000818:Animals; D051926:Basigin / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D051926:Basigin; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt
keywords: CD147; VEGF-A/VEGFR-2 signalling; hepatocytes; liver fibrosis; sinusoidal endothelial cell