Tumor‐derived tumor necrosis factor‐alpha promotes progression and epithelial‐mesenchymal transition in renal cell carcinoma cells

Pro‐inflammatory cytokines and chemokines are involved in promoting tumorigenesis by facilitating tumor proliferation and metastasis. The serum levels of interleukin (IL)‐6, IL‐1β, and tumor necrosis factor‐alpha (TNF‐α) are significantly elevated in patients with renal cell carcinoma (RCC). However...

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Published in:Cancer science 2008-05, Vol.99 (5), p.905-913
Main Authors: Chuang, Mei‐Jen, Sun, Kuang‐Hui, Tang, Shye‐Jye, Deng, Ming‐Wei, Wu, Yu‐Hsin, Sung, Jung‐Sung, Cha, Tai‐Lung, Sun, Guang‐Huan
Format: Article
Language:English
Subjects:
Biological and medical sciences
Carcinoma, Renal Cell - immunology
Carcinoma, Renal Cell - metabolism
Carcinoma, Renal Cell - pathology
Disease Progression
Epithelial Cells - metabolism
Epithelial Cells - pathology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Interleukin-1beta - metabolism
Interleukin-6 - metabolism
Kidney Neoplasms - immunology
Kidney Neoplasms - metabolism
Kidney Neoplasms - pathology
Kidneys
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism
Medical sciences
Mesoderm - pathology
Nephrology. Urinary tract diseases
Original /Report
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha - metabolism
Tumors
Tumors of the urinary system
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Summary:Pro‐inflammatory cytokines and chemokines are involved in promoting tumorigenesis by facilitating tumor proliferation and metastasis. The serum levels of interleukin (IL)‐6, IL‐1β, and tumor necrosis factor‐alpha (TNF‐α) are significantly elevated in patients with renal cell carcinoma (RCC). However, the mechanisms of how these cytokines participate in the progression of RCC remains unknown. In the present study, we investigated the effects of tumor‐derived cytokines on invasion and the epithelial‐mesenchymal transition (EMT) of RCC cells. We found that expression of IL‐1β, IL‐6, TNF‐α, hypoxia‐inducible factor‐alpha (HIF‐1α), and matrix metalloproteinase‐2 (MMP2) were significantly elevated in high malignancy A498 cells compared to low malignancy 786‐O cells. The invasion ability of A498 was three‐fold higher than that of 786‐O cells. The invasiveness of 786‐O cells was markedly enhanced by adding conditioned medium derived from A498 cells. This phenomenon was significantly inhibited by immunodepletion of TNF‐α followed by MMP2, IL‐6, or IL‐1β from A498 conditioned medium. Synergistic inhibition was also noted after simultaneous immunodepletion of TNF‐α, IL‐1β, and IL‐6. RCC cell lines with higher malignancy produced more TNF‐α, which was correlated with their stronger invasive ability. The invasiveness of 786‐O cells was significantly promoted by TNF‐α in a dose‐dependent manner. Moreover, TNF‐α induced the EMT of 786‐O cells by repressing E‐cadherin, promoting vimentin expression, and activating MMP9 activity. Our findings demonstrate that pro‐inflammatory cytokines, especially TNF‐α, can enhance invasion and the EMT of renal cancer cells, which provides a therapeutic target to prevent and treat advanced RCC. (Cancer Sci 2008; 99: 905–913)
ISSN:1347-9032
1349-7006
1349-7006
DOI:10.1111/j.1349-7006.2008.00756.x