High-mobility group box 1 activates caspase-1 and promotes... : Hepatology (original) (raw)

Hepatobiliary Malignancies

High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases

Yan, Wei1; Chang, Ying1; Liang, Xiaoyan1; Cardinal, Jon S.1; Huang, Hai1; Thorne, Stephen H.2; Monga, Satdarshan P.S.3; Geller, David A.1; Lotze, Michael T.1; Tsung, Allan1,*

1_Departments of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA_

2_Departments of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA_

3_Departments of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA_

*Address reprint requests to: Department of Surgery, University of Pittsburgh Medical Center Liver Cancer Center, 3459 Fifth Avenue, Montefiore Hospital, 7 South, Pittsburgh, PA 15213 Email:[email protected]; fax: 412–692–2002

Received 12 July 2011; Accepted 20 December 2011

Published online in Wiley Online Library (wileyonlinelibrary.com).

Grant sponsor: Howard Hughes Medical Institute Physician-Scientist Award; Grant sponsor: American College of Surgeons Research Fellowship.

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.).

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.

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.