| High mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. | |
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MedLine Citation:
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PMID: 22234969 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 TLR4 and RAGE signaling pathways. Downstream from hypoxia induced caspase-1 activation, cleavage and release of proinflammatory cytokines, IL-1β and IL-18 occurred. We further demonstrate that overexpression of HMGB1 or treatment with recombinant HMGB1 enhanced invasiveness of HCC cells while 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 subsequent production of multiple inflammatory mediators which in turn promotes cancer invasion and metastasis. (HEPATOLOGY 2012.). |
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Authors:
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Wei Yan; Ying Chang; Xiaoyan Liang; Jon S Cardinal; Hai Huang; Stephen H Thorne; Satdarshan P S Monga; David A Geller; Michael T Lotze; Allan Tsung |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-11 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 American Association for the Study of Liver Diseases. |
Affiliation:
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Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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