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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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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:BACKGROUND:NF-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. RESULTS:Immunohistochemical 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. CONCLUSION:ZAS3 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:Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth and metastasis. We have utilized mice over-expressing (Hpa-tg) heparanase to reveal the role of host heparanase in tumor initiation, growth and metastasis. While in wild type mice tumor development in response to DMBA carcinogenesis was restricted to the mammary gland, Hpa-tg mice developed tumors also in their lungs and liver, associating with reduced survival of the tumor-bearing mice. Consistently, xenograft tumors (lymphoma, melanoma, lung carcinoma, pancreatic carcinoma) transplanted in Hpa-tg mice exhibited accelerated tumor growth and shorter survival of the tumor-bearing mice compared with wild type mice. Hpa-tg mice were also more prone to the development of metastases following intravenous or subcutaneous injection of tumor cells. In some models, the growth advantage was associated with infiltration of heparanase-high host cells into the tumors. However, in other models, heparanase-high host cells were not detected in the primary tumor, implying that the growth advantage in Hpa-tg mice is due to systemic factors. Indeed, we found that plasma from Hpa-tg mice enhanced tumor cell migration and invasion attributed to increased levels of pro-tumorigenic factors (i.e., RANKL, SPARC, MIP-2) in the plasma of Hpa-Tg vs. wild type mice. Furthermore, tumor aggressiveness and short survival time were demonstrated in wild type mice transplanted with bone marrow derived from Hpa-tg but not wild type mice. These results were attributed, among other factors, to upregulation of pro-tumorigenic (i.e., IL35+) and downregulation of anti-tumorigenic (i.e., IFN-γ+) T-cell subpopulations in the spleen, lymph nodes and blood of Hpa-tg vs. wild type mice and their increased infiltration into the primary tumor. Collectively, our results emphasize the significance of host heparanase in mediating the pro-tumorigenic and pro-metastatic interactions between the tumor cells and the host tumor microenvironment, immune cells and systemic factors.

Project description:BackgroundLiver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets.MethodsTranscription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-β1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor β-aminopropionitrile (BAPN).ResultsCAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-β1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro.InterpretationOur study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy. FUND: This research was supported by the National Natural Science Foundation of China (31872740), the 100-member plan of the Shanghai Municipal Commission of Health and Family Planning (2017BR043), Shanghai Science and Technology Commission Project(17ZR1416800), Renji Hospital Training Fund (PYMDT-003, PYIII-17-015), National Natural Science Foundation of China (81672358), the Shanghai Municipal Education Commission-Gao feng Clinical MedicineGrant Support (20181708), Program of Shanghai Academic/Technology Research Leader(19XD1403400), Science and Technology Commission of Shanghai Municipality (18410721000), Shanghai Municipal Health Bureau (2018BR32), China Postdoctoral Science Foundation (2018M640403), National Natural Science Foundation of China (81701945) and Youth project of Shanghai Municipal Health Commission(20164Y0045).

Dataset Information

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

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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