title: Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis.
abstract: Activation of hepatic stellate cells (HSCs) by transforming growth factor-β1 (TGF-β1) initiates HBV-associated fibrogenesis. The mechanism of TGF-β1 modulating HSC activation is not fully uncovered. We hypothesized a positive feedback signaling loop of TGF-β1-CD147 promoting liver fibrogenesis by activation of HSCs. Human HSC cell line LX-2 and spontaneous liver fibrosis model derived from HBV transgenic mice were used to evaluate the activation of molecules in the signaling loop. Wound healing and cell contraction assay were performed to detect the CD147-overexpressed HSC migration and contraction. The transcriptional regulation of CD147 by TGF-β1/Smad4 was determined using dual-luciferase reporter assay and chromatin immunoprecipitation. We found that a positive reciprocal regulation between TGF-β1 and CD147 mediated HSC activation. CD147 over-expression promoted HSC migration and accelerated TGF-β1-induced cell contraction. Phosphorylation of Smad2 and Smad3 in cooperation with Smad4 mediated the TGF-β1-regulated CD147 expression. Smad4 activated the transcription by direct interaction with CD147 promoter. Meanwhile, CD147 modulated the activated phenotype of HSCs through the ERK1/2 and Sp1 which up-regulated α-SMA, collagen I, and TGF-β1 synthesis. These findings indicate that TGF-β1-CD147 loop plays a key role in regulating the HSC activation and combination of TGF-β receptor inhibitor and anti-CD147 antibody might be promised to reverse fibrogenesis.
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.|Department of Medical Technology, Xi'an Medical University, Xi'an, 710021 China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Di
authors.initials: D
authors.lastname: Ju
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.|Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ling-Min
authors.initials: LM
authors.lastname: Kong
authors.affiliation: Department of Pharmacogenomics, School of Pharmacy, Fourth of Military Medical University, Xi'an, 710021 China.
authors.forename: Yanhai
authors.initials: Y
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Can
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xi-Long
authors.initials: XL
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhi-Nan
authors.initials: ZN
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Huijie
authors.initials: H
authors.lastname: Bian
mesh_terms: D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D051785:Smad Proteins; D051901:Smad4 Protein; D016329:Sp1 Transcription Factor; D053773:Transforming Growth Factor beta1; D051926:Basigin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3