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- Title
High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases.
- Authors
Yan, Wei; Chang, Ying; Liang, Xiaoyan; Cardinal, Jon S; Huang, Hai; Thorne, Stephen H; Monga, Satdarshan P S; Geller, David A; Lotze, Michael T; Tsung, Allan
- 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.
- Publication
Hepatology (Baltimore, Md.), 2012, Vol 55, Issue 6, p1863
- ISSN
1527-3350
- Publication type
Journal Article
- DOI
10.1002/hep.25572