title: Stromal cell-derived factor-1/CXC receptor 4 and β1 integrin interaction regulates urokinase-type plasminogen activator expression in human colorectal cancer cells.
abstract: The stromal cell-derived factor-1 (SDF-1)/CXC receptor 4 (CXCR4) axis has been shown to play a role in colorectal cancer progression. In addition, the protease urokinase-type plasminogen activator (uPA) is an important factor in tumor cell invasion and metastasis. However, the mechanism by which SDF-1 mediates uPA expression in human colorectal cancer cells remains unknown. We investigated the molecular mechanism governing the interaction between SDF-1 stimulation and uPA expression in three human colon cancer cell lines (DLD-1, SW48, and COLO 205). We found that SDF-1 stimulation led to an increase in the expression and secretion of uPA in these cells. Experiments involving specific inhibitors and small interfering RNA demonstrated that the activation of p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways are critical for SDF-1-induced uPA expression. Analysis of transcription factor binding using ELISA and chromatin immunoprecipitation assays revealed that SDF-1 increased Sp1- and AP-1-DNA-binding activities in DLD-1 cells. Inhibition of Sp1 and AP-1 activation blocked the SDF-1-induced expression and activity of the uPA promoter. The effect of SDF-1 on DLD-1 signaling and uPA expression was mediated by the CXCR4/β1 integrin axis. In summary, our findings elucidate the mechanisms of SDF-1/CXCR4 downstream signaling and provide insights into the function of SDF-1 in colon cancer cells.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taiwan.
authors.forename: Wen-Shih
authors.initials: WS
authors.lastname: Huang
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chin
authors.forename: Cheng-Nan
authors.initials: CN
authors.lastname: Chen
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Kuo
authors.forename: Te-Chuan
authors.initials: TC
authors.lastname: Chen
authors.forename: Hong-Ren
authors.initials: HR
authors.lastname: Yu
authors.forename: Shui-Yi
authors.initials: SY
authors.lastname: Tung
authors.forename: Chien-Heng
authors.initials: CH
authors.lastname: Shen
authors.forename: Yung-Yu
authors.initials: YY
authors.lastname: Hsieh
authors.forename: Su-Er
authors.initials: SE
authors.lastname: Guo
authors.forename: Chung-Sheng
authors.initials: CS
authors.lastname: Shi
authors.forename: Ta-Ju
authors.initials: TJ
authors.lastname: Liu
authors.forename: Hsing-Chun
authors.initials: HC
authors.lastname: Kuo
mesh_terms: D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000502:physiology; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D025941:Protein Interaction Mapping / Q000379:methods*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism* / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019012:Integrin beta1; D019718:Receptors, CXCR4; D016329:Sp1 Transcription Factor; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator