Dataset Information

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

ABSTRACT: 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.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.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.Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4475488 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Yao Y Yan Wei W Tohme Samer S Chen Man M Fu Yu Y Tian Dean D Lotze Michael M Tang Daolin D Tsung Allan A

Journal of hepatology 20150212 1

<h4>Background & aims</h4>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 th ...[more]

PMID: 25681553

Similar Datasets

Project description:The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and up-regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC-1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC-1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine-induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll-like receptor-9. This binding leads to activation of p38 and subsequent phosphorylation of PGC-1α, with resultant up-regulation of mitochondrial biogenesis.ConclusionTaken together, our findings suggest that during hypoxia HMGB1 up-regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017;66:182-197).

Project description:BackgroundReprogrammed glucose metabolism, also known as the Warburg effect, which is essential for tumor progression, is regarded as a hallmark of cancer. MAP17, a small 17-kDa non-glycosylated membrane protein, is frequently dysregulated in human cancers. However, its role in hepatocellular carcinoma (HCC) remains largely unknown.MethodsImmunohistochemistry was used to analyze the expression pattern of MAP17 in HCC. Loss-of-function and gain-of-function studies were performed to investigate the oncogenic roles of MAP17 in vitro and in vivo. RNA sequencing, co-immunoprecipitation, immunofluorescence and western blotting were used to study the molecular mechanism of MAP17 affecting the tumor growth and glycolytic phenotype of HCC.ResultsAn integrative analysis showed that MAP17, a small 17-kDa non-glycosylated membrane protein, is significantly related to the glycolytic phenotype of hepatocellular carcinoma (HCC). Firstly, we found that MAP17 expression is hypoxia-dependent and predicts a poor prognosis in HCC. Genetic silencing of MAP17 reduced the rate of glucose uptake, lactate release, extracellular acidification rate, and expression of glycolytic genes. Ectopic expression of wild type MAP17 but not its PDZ binding domain mutant MAP17-PDZm increased tumor glycolysis. Further research showed that MAP17 knockdown markedly retarded in vivo tumor growth in HCC. Importantly, attenuation of tumor glycolysis by galactose largely hijacked the growth-promoting role of MAP17 in HCC cells. RNA sequencing analysis revealed that MAP17 knockdown leads to transcriptional changes in the ROS metabolic process, cell surface receptor signaling, cell communication, mitotic cell cycle progression, and regulation of cell differentiation. Mechanistically, MAP17 exerted an increased tumoral phenotype associated with an increase in reactive oxygen species (ROS), which activates downstream effectors AKT and HIF1α to enhance the Warburg effect. In HCC clinical samples, there is a close correlation between MAP17 expression and HIF1α or phosphorated level of AKT.ConclusionsOur results show that MAP17 is a novel glycolytic regulator, and targeting MAP17/ROS pathway may be an alternative approach for the prevention and treatment of HCC.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets