Tumor necrosis factor-α promotes the lymphangiogenesis of gallbladder carcinoma through nuclear factor-κB-mediated upregulation of vascular endothelial growth factor-C.

Abstract

Vascular endothelial growth factor (VEGF)-C is an important lymphangiogenic factor involved in the lymphangiogenesis of gallbladder carcinoma (GBC) and the lymph node metastasis of the tumor. Tumor necrosis factor (TNF)-α, a key inflammatory cytokine responding to chronic inflammation of GBC, has been reported to stimulate the expression of VEGF-C in some nonneoplastic cells. But whether TNF-α promotes the expression of VEGF-C in GBC has yet to be determined. Therefore, in the present study, the concentration of TNF-α and VEGF-C and the lymphatic vessel density (LVD) in the clinical GBC specimens were analyzed, and a linear correlation was found between the concentration of TNF-α and that of VEGF-C, the lymphatic vessel density (LVD); The transcription and protein level of VEGF-C in NOZ cell line were detected by real-time polymerase chain reaction (PCR) and enzyme linked immunosorbent assay (ELISA), and TNF-α enhanced the expression of VEGF-C in NOZ cell lines in a dose and time-dependent manner. Lymphatic tube formation in vitro was observed in a three-dimensional coculture system consisting of HDLECs and NOZ cell lines, and lymphatic vessels of GBC in nude mice model was detected by immunohistochemistry. TNF-α promoted the tube formation of lymphatic endothelial cells in vitro and the lymphangiogenesis of GBC in nude mice; The nuclear factor (NF)-κB binding site on the VEGF-C promoter was identified using Site-directed mutagenesis, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Taken together, TNF-α can upregulate the expression of VEGF-C and promote the lymphangiogenesis of GBC via NF-κB combining with the promoter of VEGF-C.

• Authors: Qiang Du, Lei Jiang, Xiaoqian Wang, Meiping Wang, Feifei She, Yanling Chen
• Journal: Cancer science (Cancer Sci) Vol. 105 Issue 10 Pg. 1261-71 (Oct 2014) ISSN: 1349-7006 [Electronic] England
• PMID: 25154789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• NF-kappa B
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor C

Topics

• Adult
• Aged
• Animals
• Cell Line, Tumor
• Female
• Gallbladder Neoplasms (pathology)
• Humans
• Lymphangiogenesis (drug effects)
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• NF-kappa B (physiology)
• Promoter Regions, Genetic
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation
• Vascular Endothelial Growth Factor C (genetics)