title: A chimeric antibody targeting CD147 inhibits hepatocellular carcinoma cell motility via FAK-PI3K-Akt-Girdin signaling pathway.
abstract: CD147 is expressed at low levels in normal tissues but frequently highly expressed in a wide range of tumor types such as lung, breast, and liver and therefore it is a potentially unique therapeutic target for these diverse tumor types. We previously generated a murine antibody HAb18 which suppresses matrix met al.loproteinase-2 and matrix metalloproteinase-9 secretion, attenuates cell invasion by blocking the CD147 molecule in tumor cells. Here, we generated a chimeric antibody containing the variable heavy and variable light chains of murine HAb18 and the constant regions of human IgG1γ1 and human κ chain as a potential therapeutic agent (designated cHAb18). Quantitative measurement of cHAb18 antibody affinity for antigen CD147 with surface plasmon resonance showed the equilibrium dissociation constant KD was 2.66 × 10(-10) mol/L, similar to that of KD 2.73 × 10(-10) mol/L for murine HAb18. cHAb18 induced antibody-dependent cell-mediated cytotoxicity in two hepatocellular carcinoma cell lines, SMMC-7721 and Huh-7 cells. It inhibited cancer invasion and migration in hepatocellular carcinoma cells by specifically blocking CD147. Except for the depression of matrix metalloproteinase-2 and matrix metalloproteinase-9 expressions, cHAb18 antibody suppressed cell motility by rearrangement of actin cytoskeleton, which was probably induced by decreasing the phosphorylation of focal adhesion kinase, phosphatidylinositide-3 kinase (PI3K), Akt, and Girdin in the integrin signaling pathway. In an orthotopic model of hepatocellular carcinoma in BALB/c nude mice, cHAb18 treatment effectively reduced the tumor metastasis in liver and prolonged the survival. These findings reveal new therapeutic potential for cHAb18 antibody targeting CD147 on tumor therapy.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Cell Biology and Cell Engineering Research Center, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.forename: Xiang-Min
authors.initials: XM
authors.lastname: Yang
authors.forename: Ding
authors.initials: D
authors.lastname: Wei
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Xiu-Xuan
authors.initials: XX
authors.lastname: Sun
authors.forename: Fei
authors.initials: F
authors.lastname: Feng
authors.forename: Gang
authors.initials: G
authors.lastname: Nan
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhi-Nan
authors.initials: ZN
authors.lastname: Chen
authors.forename: Huijie
authors.initials: H
authors.lastname: Bian
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D051926:Basigin / Q000276:immunology*; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003412:Cricetulus; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000276:immunology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000276:immunology / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D015398:Signal Transduction; D057127:Single-Chain Antibodies / Q000276:immunology; D022502:Stress Fibers / Q000276:immunology; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D000906:Antibodies; D051926:Basigin; D051417:Focal Adhesion Kinase 1; D006877:Hydroxamic Acids; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D033921:Vesicular Transport Proteins; C497887:Bsg protein, mouse; C527550:Ccdc88a protein, mouse; C100342:marimastat; C496051:Ptk2 protein, mouse; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse