Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma

Sun, Mingfei; Han, Xiaowei; Jia, Ming; Jiang, Weidong; Wang, Min; Zhang, Hong; Hou, Gang; Jiang, Yi

doi:10.3748/wjg.v11.i38.5931

Cited by 62 publications

(39 citation statements)

References 35 publications

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“…These results agree with the observation of a significant association of iNOS and Metalloproteinase-9 expression with HCC recurrence [121] , and iNOS overexpression with poor prognosis for gastric cancer [129] , adenoid cystic carcinoma of salivary glands [130] , fibrous histiocytoma [131] , colorectal cancer [132] . These iNOS effects seem to be mediated by its angiogenic properties and intensified by Cycloxygenase 2 (COX2) upregulation [133] .…”

Section: Inducible Nitric Oxide Synthase Signalingsupporting

confidence: 81%

“…Phosphorylated ERK activates iNos in melanoma [117] and NF-k B in HeLa cells [118] . iNOS, NF-kB, RAS, and ERK are upregulated in preneoplastic rat liver lesions [119] , dysplastic and neoplastic liver from c-Myc/TGF-α transgenic mice [120] , and human HCCs [121,122] , and elevated NO plasma levels are present in patients with cirrhosis and HCC [123] . A recent analysis of iNos function and interactions with NF-kB and Ha-RAS/ERK signalling was performed during hepatocarcinogenesis in F344 and BN rats, possessing different genetic predisposition to HCC, and TGF-α and c-Myc-TGF-α transgenic mice, characterized by different susceptibility to HCC [124] .…”

Section: Inducible Nitric Oxide Synthase Signalingmentioning

confidence: 99%

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Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Feo¹,

Frau²,

Pascale³

2008

WJG

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Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-kB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.

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Section: Inducible Nitric Oxide Synthase Signalingsupporting

confidence: 81%

Section: Inducible Nitric Oxide Synthase Signalingmentioning

confidence: 99%

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Feo¹,

Frau²,

Pascale³

2008

WJG

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“…Several studies have investigated the expression of MMPs and iNOS in human cancers and their involvement in tumor progression [44,67,68]. These enzymes are up-regulated in several invasive cancers, and their levels are correlated with tumor invasion, and metastases, indicating that these factors play a relevant role in tumor metastasis [67].…”

Section: Discussionmentioning

confidence: 99%

Insidious role of nitric oxide in migration/invasion of colon cancer cells by upregulating MMP-2/9 via activation of cGMP-PKG-ERK signaling pathways

Babykutty

Suboj

Srinivas

et al. 2012

Clin Exp Metastasis

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Nitric oxide (NO), an uncharged free radical is implicated in various physiological and pathological processes. The present study is an investigation on the effect of NO on proliferation, apoptosis and migration of colon cancer cells. Colon adenocarcinoma cells, WiDr, were used for the in vitro experiments. Tissues from colon adenocarcinoma, adjacent normal and inflammatory tissue and lymph node with metastasis were evaluated for iNOS, MMP-2/9 and Fra-1/Fra-2. NO increases the proliferation of cancer cells and simultaneously prevents apoptosis. Expression of MMP-2/9, RhoB and Rac-1 was enhanced by NO in a time dependent manner. Further, NO increased phosphorylation of ERK1/2 and induced nuclear translocation of Fra-1 and Fra-2. Electrophoretic mobility shift analysis and use of deletion mutant promoter constructs identified role of AP-1 in NO-mediated regulation of MMP-2/9. iNOS, MMP-2/9, Fra-1 and Fra-2 in normal and colon adenocarcinoma tissues were analyzed and it was found that increased expression of these proteins in cancer when compared to normal provides support to our in vitro findings. The study showed that the NO-cGMP-PKG promotes MMP-2/9 expression by activating ERK-1/2 and AP-1. This study reveals the insidious role of NO in imparting tumor aggressiveness.

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“…There are accumulating evidences that tumor angiogenesis plays an important role in the progression and metastasis of HCC, and a wide variety of angiogenic factors involved in this process [1][2][3][4][5][6]. Among the identified angiogenic factors, vascular endothelial growth factor (VEGF) is a potent angiogenic factor that plays a critical role in mediating angiogenesis in HCC [1,7].…”

Section: Introductionmentioning

confidence: 99%

The angiogenic and prognostic implications of VEGF, Ang-1, Ang-2, and MMP-9 for hepatocellular carcinoma with background of hepatitis B virus

et al. 2008

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The objective of this study was to investigate the expressions of angiogenic factors and elucidate their angiogenic and prognostic roles in hepatocellular carcinoma (HCC) with background of hepatitis B virus (HBV). We evaluated microvessel density (MVD) of HCC, and investigated immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2), and matrix metalloproteinases-9 (MMP-9) in 67 specimens of surgically resected HCC, which were all positive for hepatitis B surface antigen. We investigated the relationship between their expressions and clinicopathological factors or prognosis. The microvessel density (MVD) of tumor tissue and surrounding normal liver tissue was 93.1 +/- 43.8/mm2 and 30.4 +/- 14.8/mm2, respectively. The MVD of well-differentiated HCC was significantly less than that of poorly differentiated HCC. MVD was positively correlated with VEGF and Ang-2 expression (P = 0.0023 and 0.0265, respectively). There was less tumor recurrence in low Ang-2 and low MMP-9 group than high Ang-2 and/or high MMP-9 group (P = 0.002). In Cox regression model, portal vein thrombus and intrahepatic metastasis was the risk factors of tumor recurrence (P = 0.003 and 0.001, respectively). Our study showed that the expression of VEGF and Ang-2 were positively correlated with MVD. Ang-2 expression and/or MMP-9 expression might be a significant predictive factor for recurrence after resection in HCC patients with the background of HBV.

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Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma

Cited by 62 publications

References 35 publications

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Insidious role of nitric oxide in migration/invasion of colon cancer cells by upregulating MMP-2/9 via activation of cGMP-PKG-ERK signaling pathways

The angiogenic and prognostic implications of VEGF, Ang-1, Ang-2, and MMP-9 for hepatocellular carcinoma with background of hepatitis B virus

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