The Role of Tumor Necrosis Factor-alpha in Tumorigenesis of

• Main Authors: Yu-Hsin Wu, 吳郁欣
• Other Authors: Kuang-Hui Sun
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/50154957540327085543

碩士 === 國立陽明大學 === 醫學生物技術研究所 === 95 === Tumor necrosis factor-a (TNF-a) is a proinflammatory cytokine normally produced by macrophages. However, more and more evidence showed chronic low-dose of TNF-a stimulation could promote tumorigenesis. We previously demonstrated that high grade clear cell renal cell carcinoma (ccRCC) cell line secreted more TNF-a than low grade one, and allowed low grade cell line (786-O) gain of invasive ability. Other studies also found the plasma levels of TNF-a were increased in patients with renal cell carcinoma. Theses findings all emphasize the importance of TNF-a during renal carcinogenesis. We therefore investigated the roles of TNF-a in mediating invasion of 786-O cells. Increased invasiveness of 786-O cells was observed after TNF-a treatment. Expression of MMP9 was upregulated in the supernatant of TNF-a treated cells, revealed by gelatin zymography. This suggests that TNF-a may promote 786-O invasive capability via the induction of MMP9. Recently, epithelial-mesenchymal transition (EMT) was demonstrated to be a major mechanism responsible for mediating invasiveness and metastasis of cancers. In this report, we demonstrated that 786-O cells undergo EMT within 4 days following stimulation with TNF-a. In Western blot analyses, TNF-a induced Akt/GSK-3b/NF-kB phosphorylation in a time-dependent manner, and this correlated with NF-kB promoter activity. Since overexpression of NF-kB has been reported to induce EMT in breast cancer, we further focused on NF-kB pathway. To investigate the importance of NF-kB in ccRCC, we employed inhibitors to block NF-kB activation. EMT phenotypes were slightly reversed by the inhibitors of NF-kB, whereas inhibition of NF-kB activity had no significant effects on MMP9 expression and invasion, suggesting that there may be other mechanisms involved. These observations indicate that TNF-a could be not only a diagnostic marker, but also a prognostic marker in renal neoplasms. Besides, NF-kB may be a molecular target for developing alternative ccRCC therapeutic approaches.