title: CD24 controls Src/STAT3 activity in human tumors.
abstract: CD24 is a glycosyl-phosphatidylinositol-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties in vitro and tumor growth in vivo. However, little is known about how CD24 mediates these effects. Here we have analyzed the functional consequences of CD24 knock-down or over-expression in human cancer cell lines. Depletion of CD24 reduced cell proliferation and adhesion, enhanced apoptosis, and regulated the expression of various genes some of which were identified as STAT3 target genes. Loss of CD24 reduced STAT3 and FAK phosphorylation. Diminished STAT3 activity was confirmed by specific reporter assays. We found that reduced STAT3 activity after CD24 knock-down was accompanied by altered Src phosphorylation. Silencing of Src, similar to CD24, targeted the expression of prototype STAT3-regulated genes. Likewise, the over-expression of CD24 augmented Src-Y416 phosphorylation, the recruitment of Src into lipid rafts and the expression of STAT3-dependent target genes. An antibody to CD24 was effective in reducing tumor growth of A549 lung cancer and BxPC3 pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-phosphorylation in the tumor and altered the expression of STAT3 target genes. Our results provide evidence that CD24 regulates STAT3 and FAK activity and suggest an important role of Src in this process. Finally, the targeting of CD24 by antibodies could represent a novel route for tumor therapy.
authors: Tumor Immunology Programme, German Cancer Research Center, Heidelberg, Germany.
authors: Niko P
authors: NP
authors: Bretz
authors: Alexei V
authors: AV
authors: Salnikov
authors: Claudia
authors: C
authors: Perne
authors: Sascha
authors: S
authors: Keller
authors: Xiaoli
authors: X
authors: Wang
authors: Claudia T
authors: CT
authors: Mierke
authors: Mina
authors: M
authors: Fogel
authors: Natalie
authors: N
authors: Erbe-Hofmann
authors: Thomas
authors: T
authors: Schlange
authors: Gerhard
authors: G
authors: Moldenhauer
authors: Peter
authors: P
authors: Altevogt
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000235:genetics; D051927:CD24 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D051927:CD24 Antigen; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases