Dataset Information

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

ABSTRACT:

Aim

To investigate whether NF-kappaB is activated in human gastric carcinoma tissues and, if so, to study whether there is any correlation between NF-kappaB activity and heparanase expression in gastric carcinoma.

Methods

NF-kappaB activation was assayed by immunohistochemical staining in formalin-fixed, paraffin-embedded specimens from 45 gastric carcinoma patients. Electrophoretic mobility shift assay (EMSA) method was used for nuclear protein from these fresh tissue specimens. Heparanase gene expression was quantified using quantitative RT-PCR.

Results

The nuclear translocation of RelA (marker of NF-kappaB activation) was significantly higher in tumor cells compared to adjacent and normal epithelial cells ((41.3+/-3.52)% vs (0.38+/-0.22) %, t = 10.993, P = 0.000<0.05; (41.3+/-3.52)% vs (0+/-0.31)%, t = 11.484, P = 0.000<0.05). NF-kappaB activation was correlated with tumor invasion-related clinicopathological features such as lymphatic invasion, pathological stage, and depth of invasion (Z = 2.148, P = 0.032<0.05; chi(2) = 8.758, P = 0.033<0.05; chi(2) = 18.531, P = 0.006<0.05). NF-kappaB activation was significantly correlated with expression of heparanase gene (r = 0.194, P = 0.046<0.05).

Conclusion

NF-kappaB RelA (p65) activation was related with increased heparanase gene expression and correlated with poor clinicopathological characteristics in gastric cancers. This suggests NF-kappaB as a major controller of the metastatic phenotype through its reciprocal regulation of some metastasis-related genes.

SUBMITTER: Cao HJ

PROVIDER: S-EPMC4250607 | biostudies-literature | 2005 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Cao Hou-Jun HJ Fang Yong Y Zhang Xing X Chen Wen-Jun WJ Zhou Wen-Peng WP Wang Hong H Wang Lin-Bo LB Wu Jin-Min JM

World journal of gastroenterology 20050201 6

<h4>Aim</h4>To investigate whether NF-kappaB is activated in human gastric carcinoma tissues and, if so, to study whether there is any correlation between NF-kappaB activity and heparanase expression in gastric carcinoma.<h4>Methods</h4>NF-kappaB activation was assayed by immunohistochemical staining in formalin-fixed, paraffin-embedded specimens from 45 gastric carcinoma patients. Electrophoretic mobility shift assay (EMSA) method was used for nuclear protein from these fresh tissue specimens. ...[more]

PMID: 15682491

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Project description:BackgroundNF-kappaB binds to the kappaB motif to regulate transcription of genes involved in growth, immunity and inflammation, and plays a pivotal role in the production of pro-inflammatory cytokines after nerve injuries. The zinc finger protein ZAS3 also binds to the kappaB or similar motif. In addition to competition for common DNA sites, in vitro experiments have shown that ZAS3 can inhibit NF-kappaB via the association with TRAF2 to inhibit the nuclear translocation of NF-kappaB. However, the physiological significance of the ZAS3-mediated inhibition of NF-kappaB has not been demonstrated. The purpose of this study is to characterize ZAS3 proteins in nervous tissues and to use spinal nerve ligation, a neuropathic pain model, to demonstrate a functional relationship between ZAS3 and NF-kappaB.ResultsImmunohistochemical experiments show that ZAS3 is expressed in specific regions of the central and peripheral nervous system. Abundant ZAS3 expression is found in the trigeminal ganglion, hippocampal formation, dorsal root ganglia, and motoneurons. Low levels of ZAS3 expressions are also found in the cerebral cortex and in the grey matter of the spinal cord. In those nervous tissues, ZAS3 is expressed mainly in the cell bodies of neurons and astrocytes. Together with results of Western blot analyses, the data suggest that ZAS3 protein isoforms with differential cellular distribution are produced in a cell-specific manner. Further, neuropathic pain confirmed by persistent mechanical allodynia was manifested in rats seven days after L5 and L6 lumbar spinal nerve ligation. Changes in gene expression, including a decrease in ZAS3 and an increase in the p65 subunit of NF-kappaB were observed in dorsal root ganglion ipsilateral to the ligation when compared to the contralateral side.ConclusionZAS3 is expressed in nervous tissues involved in cognitive function and pain modulation. The down-regulation of ZAS3 after peripheral nerve injury may lead to activation of NF-kappaB, allowing Wallerian regeneration and induction of NF-kappaB-dependent gene expression, including pro-inflammatory cytokines. We propose that reciprocal changes in the expression of ZAS3 and NF-kappaB might generate neuropathic pain after peripheral nerve injury.

Project description:Background and objectiveThe nuclear factor kappa B (NF-κB) consists of a group of transcription factors of which its dysregulation is responsible for diseases such as inflammation and cancer. Ubiquitin-specific proteases (USPs) are the most prominent group among the deubiquitinases (DUBs). Their functions include control of protein stability and regulation of signaling transduction. The association between NF-κB activity and human cancer progression is evident. Still, the role of USPs in the NF-κB regulation in human cancers, especially prostate cancer, is not well understood. This review discusses on the role of USP-mediated regulation of the canonical NF-κB signaling pathway in human cancers and provides a prospect of future studies in prostate cancers.MethodsWithin the biomedical literature database, PubMed, our review team searched for keywords including USP, NF-κB signaling pathway, cancer, prostate cancer, and specific USPs such as USP1, USP2, USP3, etc. These keywords were used individually or in combinations. After screening, only mechanistic studies and articles reporting the subsequent changes in cellular behaviors were included for full-text review.Key content and findingsMost USPs function primarily as DUBs to regulate the canonical NF-κB signaling pathway. The typical K48- and K63-linked DUB activities of USPs are the best understood. These USPs are positive and negative regulators of the NF-κB activity. However, their DUB activities against polyubiquitin chains with atypical linkages have not yet been extensively studied. Furthermore, some USPs can regulate the canonical NF-κB signaling pathway via ubiquitin-independent mechanisms.ConclusionsIn the regulation of the canonical NF-κB pathway, the USPs function primarily as DUBs, but they also regulate the p65/p50 by ubiquitin-independent mechanisms. Generally, in human cancer models, USP-mediated elevation and suppression of p65/p50 activity lead to more or less malignant cellular behaviors, respectively. Given the currently unbalanced focus on K48- and K63-linked DUB activities and the context-dependent function of USPs, future research of USP-mediated NF-κB regulation in human cancers should invest more in the DUB activities against the atypical polyubiquitin chains and test known mechanisms in different cancer models.

Dataset Information

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

Aim

Methods

Results

Conclusion

Publications

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

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