title: High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases.
abstract: Hypoxia is often found in solid tumors and is associated with tumor progression and poor clinical outcomes. The exact mechanisms related to hypoxia-induced invasion and metastasis remain unclear. We elucidated the mechanism by which the nuclear-damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), released under hypoxic stress, can induce an inflammatory response to promote invasion and metastasis in hepatocellular carcinoma (HCC) cells. Caspase-1 activation was found to occur in hypoxic HCC cells in a process that was dependent on the extracellular release of HMGB1 and subsequent activation of both Toll-like receptor 4 (TLR4)- and receptor for advanced glycation endproducts (RAGE)-signaling pathways. Downstream from hypoxia-induced caspase-1 activation, cleavage and release of proinflammatory cytokines interleukin (IL)-1β and -18 occurred. We further demonstrate that overexpression of HMGB1 or treatment with recombinant HMGB1 enhanced the invasiveness of HCC cells, whereas stable knockdown of HMGB1 remarkably reduced HCC invasion. Moreover, in a murine model of HCC pulmonary metastasis, stable knockdown of HMGB1 suppressed HCC invasion and metastasis.
  
  
  CONCLUSIONS
  These results suggest that in hypoxic HCC cells, HMGB1 activates TLR4- and RAGE-signaling pathways to induce caspase-1 activation with the subsequent production of multiple inflammatory mediators, which, in turn, promote cancer invasion and metastasis.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Ying
authors.initials: Y
authors.lastname: Chang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liang
authors.forename: Jon S
authors.initials: JS
authors.lastname: Cardinal
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Thorne
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
authors.forename: David A
authors.initials: DA
authors.lastname: Geller
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D020170:Caspase 1 / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D024243:HMGB1 Protein / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D024243:HMGB1 Protein; D053583:Interleukin-1beta; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020170:Caspase 1