Abstract
The aim of this current study was to investigate the expression of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in human malignant ovarian tumors, and test TWEAK's potential role on tumor progression in cell models in-vitro. Using immunohistochemistry (IHC), we found that TWEAK and its receptor Fn14 were expressed in human malignant ovarian tumors, but not in normal ovarian tissues or in borderline/benign epithelial ovarian tumors. High levels of TWEAK expression was detected in the majority of malignant tumors (36 out of 41, 87.80%). Similarly, 35 out of 41 (85.37%) malignant ovarian tumors were Fn14 positive. In these malignant ovarian tumors, however, TWEAK/Fn14 expression was not corrected with patients' clinical subtype/stages or pathological features. In vitro, we demonstrated that TWEAK only inhibited ovarian cancer HO-8910PM cell proliferation in combination with tumor necrosis factor-α (TNF-α), whereas either TWEAK or TNF-α alone didn't affect HO-8910PM cell growth. TWEAK promoted TNF-α production in cultured THP-1 macrophages. Meanwhile, conditioned media from TWEAK-activated macrophages inhibited cultured HO-8910PM cell proliferation and invasion. Further, TWEAK increased monocyte chemoattractant protein-1 (MCP-1) production in cultured HO-8910PM cells to possibly recruit macrophages. Our results suggest that TWEAK/Fn14, by activating macrophages, could be ovarian tumor suppressors. The unique expression of TWEAK/Fn14 in malignant tumors indicates that it might be detected as a malignant ovarian tumor marker.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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Carcinoma / genetics*
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Carcinoma / metabolism
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Carcinoma / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Chemokine CCL2 / agonists
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Coculture Techniques
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Cytokine TWEAK
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Macrophage Activation / drug effects
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Receptors, Tumor Necrosis Factor / genetics*
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Receptors, Tumor Necrosis Factor / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects
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TWEAK Receptor
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factors / genetics*
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Tumor Necrosis Factors / metabolism
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Tumor Necrosis Factors / pharmacology
Substances
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Biomarkers, Tumor
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CCL2 protein, human
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Chemokine CCL2
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Cytokine TWEAK
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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TNFRSF12A protein, human
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TNFSF12 protein, human
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TWEAK Receptor
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Tumor Necrosis Factor-alpha
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Tumor Necrosis Factors
Grants and funding
This work was supported by grants from the International Collaborative Items of Ministry of Science and Technology of China (No. 2006DFA32780), Shanghai Municipal Inspiring Star Award(No. 06QA14032), Science and Technology Commission of Shanghai Municipality (No. 11DZ2211002) and National Natural Science Foundation of China (No. 81272884, No. 81072137). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.