Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

Elsharkawy, Ahmed M.; Mann, Derek A.

doi:10.1002/hep.21802

Cited by 373 publications

(285 citation statements)

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“…It has been reported that NF-κB activation is essential for inflammation and inflammation-associated cancerous changes [30]. Although NF-κB binds to a region of the COX-2 promoter known to be critical for COX-2 transcriptional activation in a number of other cell types [31,32], it is reported that NF-κB activation is not necessary for the induction of COX-2 by HBx [17].…”

Section: Discussionmentioning

confidence: 99%

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBx Δ68-117 ) neither increased intracellular ROS levels nor induced COX-2 expression. HBx 68-117 , which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calciumdependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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“…Unresolved inflammation induced-liver fbrosis leading to cirrhosis without effective control is the main risk factor for the development of HCC, termed inflammation-fibrosis-carcer axis (Elsharkawy and Mann, 2007). Recent study described that cytokines lymphotoxin a and ß and their receptor (LTbR) are upregulated in HBV-or HCVinduced hepatitis and HCC, indicating the role of sustained lymphotoxin signaling in hepatitis-induced HCC (Haybaeck et al, 2009).…”

Section: Role Of Hsc In Hcc Developmentmentioning

confidence: 99%

“…Recent study described that cytokines lymphotoxin a and ß and their receptor (LTbR) are upregulated in HBV-or HCVinduced hepatitis and HCC, indicating the role of sustained lymphotoxin signaling in hepatitis-induced HCC (Haybaeck et al, 2009). The transcriptional regulator nuclear factor-jB can act as a potential master orchestrator of the axis (Elsharkawy and Mann, 2007). In a diethylnitrosamine-induced hepatocarcinogenesis rat model, activated HSC were prominent in fibrous septa around and within dysplastic and carcinomatous nodules (Johnson et al, 1998).…”

Section: Role Of Hsc In Hcc Developmentmentioning

confidence: 99%

“…Cirrhosis renders the hepatocytes more susceptible to environmental carcinogenic factors and proinflammatory cytokines contributing to hepatocarcinogenesis. A three-step process of ''hepatitis (liver inflammation)-liver fibrosis/ cirrhosis-HCC'' is believed to be involved in hepatocarcinogenesis (Elsharkawy and Mann, 2007;Wong and Ng, 2008). Activated HSCs release paracrine factors that may promote hepatocarcinogenesis through unknown mechanisms including release of survival signals (Friedman, 2008a).…”

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confidence: 99%

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Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

Wang

Cheng

Gao

et al. 2010

The Anatomical Record

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Almost 80% of hepatocellular carcinoma (HCC) cases are associated with chronic hepatitis and cirrhosis resulting from inflammation and fibrosis. A three-step process of ''inflammation-fibrosis-carcinoma'' is believed to be involved in hepatocarcinogenesis. The activation of hepatic stellate cells (HSCs) may serve as an important mediator in the process of inflammation-fibrosis-carcinoma axis, even in tumor metastasis. A remarkable knowledge of activated HSCs in the pathology of HCC development is mostly focused on the liver fibrosis. The molecular links that connects inflammation and cancer in the activation of HSC are not completely known. This highlights urgent need to increase our understanding of the cellular and molecular mechanisms, by which activation of HSCs is involved in the hepatic inflammation, carcinogenesis, and metastasis.

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“…About 90% of HCC in patients is accompanied by hepatic cirrhosis, which results from the development of liver fibrosis (Yang and Roberts, 2010). Viral hepatitis infection leading to chronic inflammation apparently promotes fibrosis and hepatic carcinogenesis, known as the inflammation-fibrosis-cancer axis (Elsharkawy and Mann, 2007).…”

Section: Introductionmentioning

confidence: 99%

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

et al. 2011

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Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-b (TGF-b) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/ CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-b-driven pathway. A dualluciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-b coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/ Akt/GSK3b signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-b. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (r s ¼ À0.3622, P ¼ 0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (r s ¼ 0.3064, P ¼ 0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-b-PI3K/Akt-GSK3b-Snail-Slug-CD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC.

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Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

Cited by 373 publications

References 50 publications

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

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