title: Induction of chemokine receptor CXCR4 expression by transforming growth factor-β1 in human basal cell carcinoma cells.
abstract: BACKGROUND
  Higher CXCR4 expression enhances basal cell carcinoma (BCC) invasion and angiogenesis. The underlying mechanism of increased CXCR4 expression in invasive BCC is still not well understood.
  
  
  OBJECTIVE
  To investigate the mechanisms involved in the regulation of CXCR4 expression in invasive BCC.
  
  
  METHODS
  We used qRT-PCR, RT-PCR, Western blot, and flow cytometric analyses to examine different CXCR4 levels among the clinical samples, co-cultured BCC cells and BCC cells treated with recombinant transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). Immunohistochemical studies were used to demonstrate the correlation between TGF-β1 and CXCR4 expressions. The signal transduction pathway and transcriptional regulation were confirmed by treatments with chemical inhibitors, neutralizing antibodies, or short interfering RNAs, as well as luciferase reporter activity.
  
  
  RESULTS
  Invasive BCC has higher TGF-β1 and CTGF levels compared to non-invasive BCC. Non-contact dermal fibroblasts co-culture with human BCC cells also increases the expression of CXCR4 in BCC cells. Treatment with recombinant human TGF-β1, but not CTGF, enhanced the CXCR4 levels in time- and dose-dependent manners. The protein level and surface expression of CXCR4 in human BCC cells was increased by TGF-β1 treatment. TGF-β1 was intensely expressed in the surrounding fibroblasts of invasive BCC and was positively correlated with the CXCR4 expression of BCC cells. The transcriptional regulation of CXCR4 by TGF-β1 is mediated by its binding to the TGF-β receptor II and phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2)-ETS-1 pathway.
  
  
  CONCLUSIONS
  TGF-β1 induces upregulation of CXCR4 in human BCC cells by phosphorylation of ERK1/2-ETS-1 pathway.
authors.affiliation: Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Chu
authors.forename: Yi-Shuan
authors.initials: YS
authors.lastname: Sheen
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Cha
authors.forename: Yeh-Fang
authors.initials: YF
authors.lastname: Hu
authors.forename: Ching-Ting
authors.initials: CT
authors.lastname: Tan
authors.forename: Hsien-Ching
authors.initials: HC
authors.lastname: Chiu
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
authors.forename: Shiou-Hwa
authors.initials: SH
authors.lastname: Jee
mesh_terms: D002280:Basal Cell Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D012878:Skin Neoplasms / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: C527276:CXCR4 protein, human; C494041:ETS1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050784:Proto-Oncogene Protein c-ets-1; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Basal cell carcinoma; Chemokine; Invasion; Transforming growth factor