Tumor-derived tumor necrosis factor-alpha promotes progression and epithelial-mesenchymal transition in renal cell carcinoma cells
Tumor-derived tumor necrosis factor-alpha promotes progression and epithelial-mesenchymal transition in renal cell carcinoma cells
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DOI：
10.1111/j.1349-7006.2008.00756.x
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发表时间：
2008-05-01
期刊：
影响因子：
5.7
通讯作者：
Sun, Guang-Huan
中科院分区：
文献类型：
--
作者：
Chuang, Mei-Jen;Sun, Kuang-Hui;Sun, Guang-Huan
促炎细胞因子和趋化因子通过促进肿瘤的增殖和转移而促进肿瘤的发生。肾细胞癌患者血清IL-6、IL-1β和肿瘤坏死因子-α水平显著升高。然而，这些细胞因子如何参与肾癌进展的机制仍不清楚。在本研究中，我们研究了肿瘤来源的细胞因子对肾癌细胞侵袭和上皮-间充质转化(EMT)的影响。我们发现高度恶性的A498细胞中IL-1β、IL-6、TNF-α、缺氧诱导因子-α(HIF-1α)和基质金属蛋白酶-2(MMP2)的表达显著高于低度恶性的786-O细胞。A498细胞的侵袭能力是786-O细胞的3倍。加入A498细胞条件培养液后，786-O细胞的侵袭力明显增强。这一现象可被免疫耗竭的肿瘤坏死因子-α和随后的MMP2、IL-6或IL-1β从A498条件培养液中显著抑制。同时免疫去除肿瘤坏死因子-α、白介素1β和白介素6后，也观察到协同抑制作用。恶性程度越高的肾癌细胞株产生的肿瘤坏死因子-α越多，这与其较强的侵袭能力有关。肿瘤坏死因子-α对786-O细胞的侵袭力有明显的促进作用，且呈剂量依赖性。此外，肿瘤坏死因子-α通过抑制E-钙粘附素、促进波形蛋白表达和激活MMP9活性来诱导786-O细胞的EMT。我们的研究结果表明，促炎症细胞因子，尤其是肿瘤坏死因子-α，能够增强肾癌细胞的侵袭性和EMT，为防治晚期肾癌提供了一个治疗靶点。
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.