Tumor metastasis and the reciprocal regulation of heparanase gene expression by nuclear factor kappa B in human gastric carcinoma tissue

Cao, Hou-Jun; Fang, Yong; Xing, Zhou; Chen, Wenjun; Zhou, Wenpeng; Wang, Hong; Wang, Linbo; Wu, Jin-Min

doi:10.3748/wjg.v11.i6.903

Cited by 25 publications

(23 citation statements)

References 13 publications

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“…Here, we found the NF-kB subunit RelA to be overexpressed in roughly half of a large set of pancreatic adenocarcinomas analysed. Overexpression of cytoplasmic and/or nuclear RelA in tumour tissue has been previously observed in larger study cohorts of gastric (Sasaki et al, 2001;Yamanaka et al, 2004;Cao et al, 2005;Lee et al, 2005), prostate (Fradet et al, 2004;Ismail et al, 2004;Ross et al, 2004; Figure 2 Kaplan -Meier survival curves in dependence of clinicopathological factors and RelA/p65 expression patterns. Overall survival dependent on nodal status (A) and grade (B).…”

Section: Discussionmentioning

confidence: 59%

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

et al. 2007

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Activation of nuclear factor-kB (NF-kB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kB subunit, in these carcinomas and possible correlations thereof with NF-kB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kB pathway in 11 tumours by quantitative PCR for NF-kB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.

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Section: Discussionmentioning

confidence: 59%

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

et al. 2007

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“…Moreover, it has been reported that NF-κB activation upregulates HPSE expression in several tumors [9][10][11][12] . Therefore, we further investigated the relationship between HPSE and NF-κB in melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, the relationship between HPSE and NF-κB is under controversial. Previous data reported that NF-κB activation upregulates HPSE expression in several tumours [9][10][11][12] . Recently, focusing on the regulatory relationship between HPSE and NF-κB in glioblastoma cells, questioned their connection 44 .…”

Section: Discussionmentioning

confidence: 99%

“…MMP-9 is known to be transcriptionally regulated by NF-κB signaling pathway 7,8 . Notably, other reports suggest a connection between HPSE and the regulation of NF-κB related genes [9][10][11][12] . In addition to the enzymatic functions, non-enzymatic activity of HPSE enhances Akt signaling and stimulates phosphatidylinositol 3-kinase (PI3K)-dependent migration and invasion of endothelial cells 13 and up-regulates the expression of VEGF in several tumor cell lines via the Src pathway 14 .…”

Section: Introductionmentioning

confidence: 99%

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Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

et al. 2015

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Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and glycocalyx thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of HPSE duality in malignant melanoma in vitro as well as in mouse melanoma models basing on the intradermal injection of transfected melanoma cells. In line with its extracellular action, HPSE-deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of VEGF affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-and most prominently MMP-9 upon HPSE knockdown. In vivo, HPSE-deficiency was related to increased lymph node metastasis. While inhibition of its extracellular function heparin was unable to block the gene regulatory impact of HPSE we proposed an intracellular mechanism. Immunostainings revealed a counter-staining of HPSE and NF-B in the nucleus suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual identity of HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor suppressive nuclear action. Identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells envisions new therapeutic options. AbstractHeparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and glycocalyx thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression.Therefore, we investigated the relevance of HPSE duality in malignant melanoma in vitro as well as in mouse melanoma models basing on the intradermal injection of transfected melanoma cells. In line with its extracellular action, HPSE-deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of VEGF affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-α and most prominently MMP-9 upon HPSE knockdown. In vivo, HPSE-deficiency was related to increased lymph node metastasis.While inhibition of its extracellular function heparin was unable to block the gene regulatory impact of HPSE we proposed an intracellular mechanism. Immunostainings revealed a counter-staining of HPSE and NF-κB in the nucleus suggesting a close relationship between both proteins. This finding was further supported by the discovery of a dir...

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“…Nuclear factor κB (NFκB) is a eukaryotic transcription factor involved in a wide range of cellular processes in response to stimuli. A study on gastric carcinoma reported a positive correlation between NFκB and heparanase expression (20). We investigated whether NFκB expression is correlated with heparanase expression in glioblastoma and, if so, how NFκB expression would be regulated.…”

Section: Introductionmentioning

confidence: 99%

Heparanase expression is associated with histone modifications in glioblastoma

et al. 2011

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Abstract. In this study we investigated epigenetic modifications such as DNA methylation, histone acetylation and histone methylation in the regulation of heparanase expression in glioblastoma. We found that heparanase promoters are differentially methylated among three glioblastoma cell lines; however, all these cells expressed baseline levels of heparanase. 5-Aza-2'-deoxycytidine (5-Aza-dC), a DNA methyltransferase inhibitor, revoked heparanase expression in all the examined cells. Trichostatin A (TSA), a histone deacetylase inhibitor, activated heparanase expression in promoter unmethylated LN229 and T98G cells but not in promoter methylated U251n cells. To identify the mechanisms of heparanase induction by 5-Aza-dC, heparanase expression-related transcription factors were examined. No detected transcription factors (EGR1, Ets1, GABPα and Sp1) were found to be induced either by 5-Aza-dC or TSA. Furthermore, we found that 5-Aza-dC increased acetylation of histone H3 and di-methylation of histone H3 lysine K4 (H3K4me2) in LN229 and T98G cells. The increased histone acetylation and H3K4me2 were also observed in heparanaseexpressing tumor tissues by immunohistochemistry staining. Additionally, we found that nuclear factor κB (NFκB) p65 but not NFκB p50 was correlated with heparanase expression, which could be expressed both by neoplastic cells and angiogenesis-related neovessel cells. However, we did not observe any regulatory mechanism between heparanase and NFκB p65 via transient transfection of their cDNA in T98G and U251n cells. We concluded that heparanase expression is associated with histone modifications and promoter DNA methylation plays a role in the control of gene silencing. Overexpression of both heparanase and NFκB p65 may be the result of excessive histone modifications.

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Tumor metastasis and the reciprocal regulation of heparanase gene expression by nuclear factor kappa B in human gastric carcinoma tissue

Cited by 25 publications

References 13 publications

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

Heparanase expression is associated with histone modifications in glioblastoma

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