title: Invasion potential of H22 hepatocarcinoma cells is increased by HMGB1-induced tumor NF-κB signaling via initiation of HSP70.
abstract: The functional relationship and cross-regulation between damage-associated molecular patterns and NF‑κB in the tumor microenvironment remains unclear. In the present study, high-mobility group protein B1 (HMGB1) was secreted in response to feed second phase of NF‑κB activation from heat shock protein (HSP) 70 that may result in a higher invasion potential of hepatocarcinoma cells. HSP70 promoted the proliferation of H22 hepatocarcinoma cells through Toll-like receptor (TLR) 2 and TLR4 signaling and induced the early phosphorylation of NF-κB, which reached maximum levels within 30 min. However, HSP70 promoted the upregulation of Beclin-1 expression via Jun N-terminal kinase (JNK) activation in tumor cells and the release of HMGB1 from tumor cells. Inhibition of Beclin-1/c-JNK production prevented the second, but not the first, phase of NF-κB phosphorylation, implicating Beclin-1/c-JNK in the second phase of phosphorylation. HSP70 induced Beclin-1-derived HMGB1 production at 4 h, which occurred before the rise in the second phosphorylation that occurred at 6 h. Exogenous HMGB1 also induced the rapid phosphorylation of NF-κB and upregulated the expression of MMP-9, inhibited the rapid phosphorylation of NF-κB and reduced MMP-9 by receptor for advanced glycation end products (RAGE) inhibitor that prevented HMGB1-induced cell invasion in vitro, which demonstrated that the biological significance of HMGB1/RAGE is key to the second, but not the first, phase of NF-κB phosphorylation in tumor cells. HSP70 triggered a positive feedback loop of NF-κB activation in H22 cells. The second phase of NF-κB phosphorylation mediated by HSP70 is implicated in the increase of tumor cell malignant invasion.
authors.affiliation: Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, Hubei 441021, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Wang
authors.forename: Guo-Xi
authors.initials: GX
authors.lastname: Chen
authors.forename: Yu-Qiao
authors.initials: YQ
authors.lastname: Liu
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Gu
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9