title: The role of MAPK-ERK pathway in 67-kDa laminin receptor-induced FasL expression in human cholangiocarcinoma cells.
abstract: OBJECTIVE
  Cancer cells are thought to possess immune evasion properties due to FasL overexpression in many types of human tumors. In the present study, we set out to investigate the role of MAPK-ERK pathway in 67-kDa laminin receptor induced FasL expression and FasL-mediated apoptosis in human cholangiocarcinoma cells.
  
  
  METHODS
  The expression of FasL and its promoter activity in cultured cholangiocarcinoma cells were examined after treatment with laminin or transfection with plasmids containing siRNA targeted to 67-kDa laminin receptor. The effects of MAPK-ERK cascade inhibitor and c-Myc inhibition by siRNA on 67-kDa laminin receptor-induced FasL expression were determined. Apoptosis assay was performed to analyze the apoptosis of lymphocytes cocultured with cholangiocarcinoma cells treated with or without MAPK-ERK cascade inhibitor.
  
  
  RESULTS
  Our results revealed that the specific MAPK-ERK cascade inhibitor, PD98059, significantly attenuated phosphorylation of c-Myc on Ser-62 and FasL upregulation in QBC-939 cells and these cells showed decreased cytotoxicity against Fas-sensitive Jurkat T cells. A luciferase reporter assay revealed that FasL promoter activity was significantly reduced in cells treated with PD98059 or transfected with c-Myc siRNA.
  
  
  CONCLUSIONS
  Based on these results, we conclude that 67LR induces FasL expression and cytotoxicity against Fas-sensitive Jurkat T cells in human cholangiocarcinoma cells through the phosphorylation of c-Myc on Ser-62 and the subsequent activation of the FasL promoter through the ERK pathway.
authors.affiliation: Hepatobiliary Surgery Hospital and Institute, Southwest Hospital, Third Military Medical University, 400038, Chongqing, China.
authors.forename: Shi-Gang
authors.initials: SG
authors.lastname: Duan
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
authors.forename: Da-Jiang
authors.initials: DJ
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Li
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000502:physiology; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D017474:Receptors, Laminin / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005419:Flavonoids; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C510624:RPSA protein, human; D017474:Receptors, Laminin; D012269:Ribosomal Proteins; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one