Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9

Yao Liu, Wei Yan, Samer Tohme, Man Chen, Yu Fu, Dean Tian, Michael Lotze, Daolin Tang, Allan Tsung

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Background & Aims The mechanisms of hypoxia-induced tumor growth remain unclear. Hypoxia induces intracellular translocation and release of a variety of damage associated molecular patterns (DAMPs) such as nuclear HMGB1 and mitochondrial DNA (mtDNA). In inflammation, Toll-like receptor (TLR)-9 activation by DNA-containing immune complexes has been shown to be mediated by HMGB1. We thus hypothesize that HMGB1 binds mtDNA in the cytoplasm of hypoxic tumor cells and promotes tumor growth through activating TLR9 signaling pathways. Methods C57BL6 mice were injected with Hepa1-6 cancer cells. TLR9 and HMGB1 were inhibited using shRNA or direct antagonists. HuH7 and Hepa1-6 cancer cells were investigated in vitro to determine how the interaction of HMGB1 and mtDNA activates TLR9 signaling pathways. Results During hypoxia, HMGB1 translocates from the nucleus to the cytosol and binds to mtDNA released from damaged mitochondria. This complex subsequently activates TLR9 signaling pathways to promote tumor cell proliferation. Loss of HMGB1 or mtDNA leads to a defect in TLR9 signaling pathways in response to hypoxia, resulting in decreased tumor cell proliferation. Also, the addition of HMGB1 and mtDNA leads to the activation of TLR9 and subsequent tumor cell proliferation. Moreover, TLR9 is overexpressed in both hypoxic tumor cells in vitro and in human hepatocellular cancer (HCC) specimens; and, injection in mice to knockdown either HMGB1 or TLR9 from HCC cells suppressed tumor growth in vivo. Conclusions Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth.

Original languageEnglish (US)
Article number5550
Pages (from-to)114-121
Number of pages8
JournalJournal of Hepatology
Volume63
Issue number1
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

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Toll-Like Receptor 9
HMGB1 Protein
Mitochondrial DNA
Hepatocellular Carcinoma
Growth
Neoplasms
Cell Proliferation
Liver Neoplasms
Hypoxia
Antigen-Antibody Complex
Cytosol
Small Interfering RNA
Mitochondria
Cytoplasm

Keywords

  • DAMPs
  • Hepatocellular carcinoma
  • HMGB1
  • Hypoxia
  • Liver
  • Mitochondrial DNA

ASJC Scopus subject areas

  • Hepatology

Cite this

Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. / Liu, Yao; Yan, Wei; Tohme, Samer; Chen, Man; Fu, Yu; Tian, Dean; Lotze, Michael; Tang, Daolin; Tsung, Allan.

In: Journal of Hepatology, Vol. 63, No. 1, 5550, 01.07.2015, p. 114-121.

Research output: Contribution to journalArticle

Liu, Yao ; Yan, Wei ; Tohme, Samer ; Chen, Man ; Fu, Yu ; Tian, Dean ; Lotze, Michael ; Tang, Daolin ; Tsung, Allan. / Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. In: Journal of Hepatology. 2015 ; Vol. 63, No. 1. pp. 114-121.
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AB - Background & Aims The mechanisms of hypoxia-induced tumor growth remain unclear. Hypoxia induces intracellular translocation and release of a variety of damage associated molecular patterns (DAMPs) such as nuclear HMGB1 and mitochondrial DNA (mtDNA). In inflammation, Toll-like receptor (TLR)-9 activation by DNA-containing immune complexes has been shown to be mediated by HMGB1. We thus hypothesize that HMGB1 binds mtDNA in the cytoplasm of hypoxic tumor cells and promotes tumor growth through activating TLR9 signaling pathways. Methods C57BL6 mice were injected with Hepa1-6 cancer cells. TLR9 and HMGB1 were inhibited using shRNA or direct antagonists. HuH7 and Hepa1-6 cancer cells were investigated in vitro to determine how the interaction of HMGB1 and mtDNA activates TLR9 signaling pathways. Results During hypoxia, HMGB1 translocates from the nucleus to the cytosol and binds to mtDNA released from damaged mitochondria. This complex subsequently activates TLR9 signaling pathways to promote tumor cell proliferation. Loss of HMGB1 or mtDNA leads to a defect in TLR9 signaling pathways in response to hypoxia, resulting in decreased tumor cell proliferation. Also, the addition of HMGB1 and mtDNA leads to the activation of TLR9 and subsequent tumor cell proliferation. Moreover, TLR9 is overexpressed in both hypoxic tumor cells in vitro and in human hepatocellular cancer (HCC) specimens; and, injection in mice to knockdown either HMGB1 or TLR9 from HCC cells suppressed tumor growth in vivo. Conclusions Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth.

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