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-1 beta, and tumor necrosis factor-alpha (TNF-alpha) 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-1 beta, IL-6, TNF-alpha, hypoxia-inducible factor-alpha (HIF-1 alpha), 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-alpha followed by MMP2, IL-6, or IL-1 beta from A498 conditioned medium. Synergistic inhibition was also noted after simultaneous immunodepletion of TNF-alpha, IL-1 beta, and IL-6. RCC cell lines with higher malignancy produced more TNF-alpha, which was correlated with their stronger invasive ability. The invasiveness of 786-O cells was significantly promoted by TNF-alpha in a dose-dependent manner. Moreover, TNF-alpha 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-alpha, can enhance invasion and the EMT of renal cancer cells, which provides a therapeutic target to prevent and treat advanced RCC.
Chuang
Mei-Jen
MJ
Graduate Institute of Life Sciences, Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, 114, Taiwan.
Sun
Kuang-Hui
KH
Tang
Shye-Jye
SJ
Deng
Ming-Wei
MW
Wu
Yu-Hsin
YH
Sung
Jung-Sung
JS
Cha
Tai-Lung
TL
Sun
Guang-Huan
GH
D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008648:Mesoderm / Q000473:pathology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9