Article first published online: 29 MAY 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 55, Issue 6, pages 1863–1875, June 2012
How to Cite
Yan, W., Chang, Y., Liang, X., Cardinal, J. S., Huang, H., Thorne, S. H., Monga, S. P.S., Geller, D. A., Lotze, M. T. and Tsung, A. (2012), High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology, 55: 1863–1875. doi: 10.1002/hep.25572
Potential conflict of interest: Nothing to report.
This work was supported by a Howard Hughes Medical Institute Physician-Scientist Award (to A.T.) and an American College of Surgeons Research Fellowship (to A.T.).
- Issue published online: 29 MAY 2012
- Article first published online: 29 MAY 2012
- Accepted manuscript online: 11 JAN 2012 04:49AM EST
- Manuscript Accepted: 20 DEC 2011
- Manuscript Received: 12 JUL 2011
- Howard Hughes Medical Institute Physician-Scientist Award
- American College of Surgeons Research Fellowship
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. Conclusion: 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. (HEPATOLOGY 2012;55:1866–1875)