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Liu Y.,University of Pittsburgh | Liu Y.,First Affiliated Hospital of Gannan Medical College | Yan W.,University of Pittsburgh | Yan W.,Huazhong University of Science and Technology | And 7 more authors.
Journal of Hepatology | Year: 2015

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. © 2015 European Association for the Study of the Liver. Source

Pan J.-P.,Huazhong University of Science and Technology | Zhang H.-Q.,First Affiliated Hospital of Gannan Medical College | Wei-Wang,Huazhong University of Science and Technology | Guo Y.-F.,Huazhong University of Science and Technology | And 3 more authors.
Brain Research | Year: 2011

ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) enhances cognitive functions; however, the underlying molecular mechanism remains unclear. Compelling evidence suggests that the endocannabinoid/endovanilloid systems play a pivotal role in regulating cognitive function. Thus, to correlate the effect of DHA on cognitive performance with the expression of endocannabinoid and endovanilloid receptors, we supplemented the diet of rats with DHA and performed in vitro experiments that focused on the endocannabinoid/endovanilloid receptors. We found that in vivo supplementation with an appropriate dose of DHA (150 or 300 mg/kg/d) significantly improved learning and memory but that a higher intake (600 mg/kg/d) increased the risk of memory impairment. In addition, we found that some subtypes of endocannabinoid/endovanilloid receptors (cannabinoid [CB] and transient receptor potential vanilloid [TRPV] receptors) were regulated in vitro by different concentrations of DHA in primary hippocampal neuron culture medium. Real-time polymerase chain reaction and western blot analysis showed that expression of both CB1 and TRPV1 was upregulated in a dose-dependent manner and reached a maximum level at 30 μmol/L (CB1) and 60 μmol/L (TRPV1) DHA. However, TRPV2 expression was downregulated in a dose-dependent fashion, and the peak of TRPV2 suppression was observed at 60 μmol/L. The dose-dependent effects of DHA on the expression of these receptors were well correlated with DHA's effect on spatial memory. Meanwhile, CB2, TRPV3, and TRPV4 expressions were not altered at diverse concentrations of DHA. We concluded that some subtypes of endocannabinoid/endovanilloid receptors might be involved in enhanced spatial memory induced by DHA supplementation. © 2011 Elsevier B.V. All rights reserved. Source

Wan D.,Soochow University of China | He S.,Soochow University of China | Xie B.,First Affiliated Hospital of Gannan Medical College | Gu W.,Soochow University of China | And 5 more authors.
Medical Oncology | Year: 2013

Aberrant miR-199a-3p expression has been reported in several cancers. However, the clinical significance of miR-199a-3p in human colorectal cancer has not been addressed. In this study, we detected miR-199a-3p expression in 92 colorectal cancer cases to evaluate its clinicopathologic characteristics in colorectal cancer. We showed that miR-199a-3p expression was significantly upregulated in cancer tissues than NATs. Clinicopathologic analysis revealed that high miR-199a-3p expression contributed to more advanced lymphatic invasion, lymph node metastasis, liver metastases and late TNM stage in colorectal cancer. Kaplan-Meier analysis showed that high expression of miR-199a-3p could lead to a significantly shorter overall survival rate. Cox's proportional hazards model also indicated that the high expression of miR-199a-3p could serve as an independent and significant prognostic factor for survival. We transfected miR-199a-3p inhibitor into SW480 cells and observed that miR-199a-3p inhibitor could markedly inhibit the cell proliferation. Flow cytometry analysis also found that miR-199a-3p inhibitor could cause G0/G1 arrest, decreased percentage of S and G2/M phase and induce more cell apoptosis in SW480 cells. These results suggested that miR-199a-3p may serve as an efficient biomarker for diagnosis and novel prognostic indicator in colorectal cancer. © 2013 Springer Science+Business Media New York. Source

Zhang Z.B.,First Hospital of Changsha | Li Z.G.,First Affiliated Hospital of Gannan Medical College
Neurochemical Research | Year: 2012

Cathepsin B, one of major lysosomal cathepsins, and JNK, a downstream component of Rho kinase (ROCK), are two families of proteases, which play an important role in ischemic cell apoptosis. However, the interrelationship between Cathepsin B and JNK in apotosis has not been examined. In the present study, rats were decapitated at 0, 2, 6, 24, 48 h of reperfusion after 2 h of middle cerebral artery occlusion (MCAO); TUNEL-positive cells appeared in the ipsilateral preoptic region during reperfusion after 2-h MCAO, and gradually increased to a peak of 24 h after reperfusion; Phospho-JNK (p-JNK) immunoreactivity, occurring after Cathepsin B expression, was gradually increased and peaked altogether with Cathepsin B at 6-h reperfusion; Fasudil (5 mg/kg, intraperitoneally), an inhibitor of ROCK, decreased the level of p-JNK and apoptotic neurons, and had no effect on cathepsin B; Immunofluorescent double labeling showed that the colocalization of cathepsin B with p-JNK appeared in the preoptic region at 2, 6, 24, 48 h of reperfusion. These findings indicate that a signal transduction pathway by ischemia-reperfusion is most likely to exist: lysosomal cathepsin B-Rho/Rho kinase pathway-JNK signaling pathway-mitochondrial-dependent intrinsic pathway. © Springer Science+Business Media, LLC 2012. Source

Chen M.,University of Pittsburgh | Chen M.,Huazhong University of Science and Technology | Liu Y.,University of Pittsburgh | Liu Y.,First Affiliated Hospital of Gannan Medical College | And 8 more authors.
Cancer Research | Year: 2015

Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage-associated molecular patterns (DAMP), such as high-mobility group box 1 (HMGB1), and dysregulated miRNAs involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in overexpression of miR-21. These changes were found to be dependent on the IL6/STAT3 signaling axis. Invasion and migration of HCC cells in vitro were inhibited by both STAT3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a posttranscriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1- mediated HCC progression through the IL6/Stat3-miR-21 axis. © 2015 American Association for Cancer Research. Source

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