title: Lipopolysaccharide initiates a bypass feedback loop of epidermal growth             factor receptor signaling by HPS70-induced COX-2 in H22 hepatocarcinoma cells.
abstract: LPS can induce TACE upregulation via signaling from TLR4-derived EGFR activation             in tumor cells. The regulation and activity of TACE have been investigated with             the observation that gene expression is upregulated in response to LPS followed             by EGFR activation, however, the process remains poorly understood. In this study,             we examined the effects of LPS on H22 hepatocarcinoma cells that displayed constitutively             active TLR4 expression. Upon TLR4 shRNA transfection into H22 cells, HSP70 expression             significantly increased. However, LPS induced early phosphorylation of EGFR in             H22 cells, which reached maximum levels within 30 min. Inhibition of TLR4 in H22             cells resulted in a significant rise in both EGFR phosphorylation and TACE upregulation             24 h after exposure to LPS. Exogenous HSP70 also induced rapid phosphorylation             of EGFR, upregulated the expression of COX-2 via a signaling pathway that involved             TACE-dependent TGF-α release. Furthermore, inhibition of EGFR activation and reduction             of COX-2 expression by COX-2 inhibitor prevented HSP70-induced cell invasion in             vitro. These findings demonstrate that the biological importance of HSP70/COX-2             is crucial to the second, but not the first, phase of EGFR phosphorylation in             tumor cells. The growth of tumor cells by inserting shRNA plasmid TLR4 combination             with COX-2 inhibitor could be effectively reduced in LPS stimulation. We concluded             that LPS triggered a bypass feedback loop of EGFR activation and involved HSP70/COX-2             in H22 cells by inhibition of TLR4 and that EGFR phosphorylation is implicated             in tumor growth by LPS stimulation.
authors.affiliation: Department of Oncology, Xiangfan Hospital, Xiangfan College, Xiangfan 441021, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Jiu Liang
authors.initials: JL
authors.lastname: Zhang
authors.forename: Xiao Juan
authors.initials: XJ
authors.lastname: Yan
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Zhi Yong
authors.initials: ZY
authors.lastname: Wang
authors.forename: Tie Nan
authors.initials: TN
authors.lastname: Yi
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008113:Liver Neoplasms; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009578:Nitrobenzenes / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse