The Role of NF-κB in Hepatitis B Virus X Protein-Mediated Upregulation of VEGF and MMPs

Liu, Liping; Liang, Huifang; Chen, Xiaoping; Zhang, Wanguang; Yang, Shengli; Xu, Tao; Li, Ren

doi:10.3109/07357900903405959

Cited by 65 publications

(46 citation statements)

References 34 publications

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“…The stimulation of CD95L on tumor cells can activate the NF-kB and ERK pathways (13), and the activation of NF-kB and ERK increases MMP9 expression (8,27). Similarly, EXO stimulation activated the NF-kB and ERK pathways in B16 cancer cells, which was demonstrated by the increased phosphorylation of NFkB and ERK in response to EXO stimulation but not EXOcont stimulation (Fig.…”

Section: Exo Promoted Mmp9 Expression and Tumor Cell Invasion Throughmentioning

confidence: 78%

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Cai

Yang

et al. 2012

The Journal of Immunology

224

174

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Activated T cells release bioactive Fas ligand (FasL) in exosomes, which subsequently induce self-apoptosis of T cells. However, their potential effects on cell apoptosis in tumors are still unknown. In this study, we purified exosomes expressing FasL from activated CD8+ T cell from OT-I mice and found that activated T cell exosomes had little effect on apoptosis and proliferation of tumor cells but promoted the invasion of B16 and 3LL cancer cells in vitro via the Fas/FasL pathway. Activated T cell exosomes increased the amount of cellular FLICE inhibitory proteins and subsequently activated the ERK and NF-κB pathways, which subsequently increased MMP9 expression in the B16 murine melanoma cells. In a tumor-invasive model in vivo, we observed that the activated T cell exosomes promoted the migration of B16 tumor cells to lung. Interestingly, pretreatment with FasL mAb significantly reduced the migration of B16 tumor cells to lung. Furthermore, CD8 and FasL double-positive exosomes from tumor mice, but not normal mice, also increased the expression of MMP9 and promoted the invasive ability of B16 murine melanoma and 3LL lung cancer cells. In conclusion, our results indicate that activated T cell exosomes promote melanoma and lung cancer cell metastasis by increasing the expression of MMP9 via Fas signaling, revealing a new mechanism of tumor immune escape.

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Section: Exo Promoted Mmp9 Expression and Tumor Cell Invasion Throughmentioning

confidence: 78%

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Cai

Yang

et al. 2012

The Journal of Immunology

224

174

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“…Thus, increased expression of CA9 results in the development of HCC by contributing to the survival of hepatocytes infected with HBV in the fibrotic liver parenchyma (Holotnakova et al, 2010). Moreover, HBx protein plays an important role in facilitating invasion and metastasis by enhancing cellular migration through up-regulation of transcription of matrix metalloproteinase 2 (MMP-2), MMP-9, MMP-3, MMP14, MT1-MMP, and cyclooxygenase-2 (COX-2) (Lara-Pezzi et al, 2002;Liu et al, 2010b;Ou et al, 2007). MMPs degrade extracellular matrix components, thereby contributing to physiological events (wound healing, and angiogenesis) and pathological conditions (cancer and arthritis).…”

Section: Effects Of Hbx Protein On Signal Transduction and Transcriptmentioning

confidence: 99%

Hepatitis B virus-induced hepatocellular carcinoma: The role of the virus x protein

Motavaf¹,

Safari²,

Jourshari³

et al. 2013

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Summary. -Hepatocellular carcinoma (HCC) is one of the most common malignant diseases and has the fourth highest mortality rate worldwide. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in HCC. Currently available evidence support a critical role of hepatitis B virus x (HBx) gene and protein in the pathogenesis of HBV-induced HCC. HBx protein is a multifunctional regulator that modulates cellular signal transduction pathways, transcriptional regulations, cell cycle progress, DNA repair, apoptosis, and genetic stability by interacting with different host factors. This review describes the current state of knowledge about the biological roles of this protein in the development of HCC. Abbreviations: DNMTs = DNA methyltransferases; HBV = hepatitis B virus; HBx = hepatitis B x protein; HCC = hepatocellular carcinoma; MMP = matrix metalloproteinase; MTA = metastasisassociated protein; RAR-β2 = retinoic acid receptor β2; TSGs = tumor suppressor genes; XPB = xeroderma pigmentosum B

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“…The cells were harvested for protein isolation. Western blot analysis was conducted as previously described (18).…”

Section: Western Blottingmentioning

confidence: 99%

Sorafenib Inhibits Hypoxia-Inducible Factor-1α Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma

Liu

Chen

et al. 2012

Clinical Cancer Research

Self Cite

112

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Purpose: The overexpression of hypoxia-inducible factor 1a (HIF-1a) is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has shown significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the antiangiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1a expression and activation in HCC cells and xenografts.Experimental Design: HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and quantitative PCR array were used to determine protein and mRNA expression, respectively. HIF-1a activity, de novo protein synthesis, and VEGF secretions were determined using assay kits.Results: Sorafenib dose dependently decreased the hypoxia-induced accumulation and activation of HIF1a protein. Further analysis revealed that such reduction of HIF-1a was associated with the inhibition of HIF-1a protein synthesis rather than the promotion of HIF-1a protein degradation or the reduction of HIF1a mRNA. Moreover, the phosphorylation levels of mTOR, extracellular signal-regulated kinase (ERK), p70S6K, RP-S6, 4E-BP1, and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1a and VEGF proteins, leading to a decrease in tumor vascularization and growth of the xenografts.Conclusions: Sorafenib-mediated inhibition of HIF-1a synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's antiangiogenic mechanism of action by inhibiting HIF-1a and VEGF protein expression. Clin Cancer Res; 18(20); 5662-71. Ó2012 AACR.

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The Role of NF-κB in Hepatitis B Virus X Protein-Mediated Upregulation of VEGF and MMPs

Cited by 65 publications

References 34 publications

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Hepatitis B virus-induced hepatocellular carcinoma: The role of the virus x protein

Sorafenib Inhibits Hypoxia-Inducible Factor-1α Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma

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