title: Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFκB signaling pathway in gastric cancer cells.
abstract: BACKGROUND
  Stromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells.
  
  
  RESULTS
  Human gastric cancer cell lines were exposed to doses of resistin; SDF-1 expression and secretion levels were then determined. Real-time polymerase chain reaction and western blotting analyses were performed to clarify molecular changes. Inhibition of Toll-like receptor 4 (TLR4) by a competitive antagonist inhibited resistin-induced SDF-1 expression. Pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that activation of the p38 mitogen-activated protein kinase (MAPK) pathway is critical for resistin-induced SDF-1 expression mediated by TLR4. The promoter activity and transcription factor enzyme-linked immunosorbent assay revealed that resistin induced expression of SDF-1 mediated by NF-κB in gastric cancer cells. Inhibition of p38 MARK activation blocked the SDF-1-induced expression and the SDF-1 promoter activity in the cancer gastric cells. Chromatin immunoprecipitation assay revealed that inhibition of p38 MARK activation also blocked the resistin-increased NF-κB-DNA-binding activity.
  
  
  CONCLUSIONS
  Resistin-induced SDF-1 upregulation by activation of TLR4, p38 MARK and NF-κB may explain a new role of resistin in the link of obesity and gastric cancer.
authors.forename: Yung-Yu
authors.initials: YY
authors.lastname: Hsieh
authors.forename: Chien-Heng
authors.initials: CH
authors.lastname: Shen
authors.forename: Wen-Shih
authors.initials: WS
authors.lastname: Huang
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chin
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Kuo
authors.forename: Meng Chiao
authors.initials: MC
authors.lastname: Hsieh
authors.forename: Hong-Ren
authors.initials: HR
authors.lastname: Yu
authors.forename: Te-Sheng
authors.initials: TS
authors.lastname: Chang
authors.forename: Tseng-Hsi
authors.initials: TH
authors.lastname: Lin
authors.forename: Yung-Wei
authors.initials: YW
authors.lastname: Chiu
authors.forename: Cheng-Nan
authors.initials: CN
authors.lastname: Chen
authors.affiliation: Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan. guscsi@gmail.com.
authors.forename: Hsing-Chun
authors.initials: HC
authors.lastname: Kuo
authors.forename: Shui-Yi
authors.initials: SY
authors.lastname: Tung
mesh_terms: D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D052243:Resistin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D016328:NF-kappa B; D009363:Neoplasm Proteins; C499624:RETN protein, human; D052243:Resistin; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases