State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University Xi'an 710032, Shaanxi Province, People's Republic of China.
Carcinogenesis. 2012 Nov;33(11):2250-9. doi: 10.1093/carcin/bgs249. Epub 2012 Jul 25.
The proliferation-specific transcription factor Forkhead box M1 (FoxM1) acts as a master regulator of cancer cell growth and survival and plays an important role in the development of hepatocellular carcinoma. However, the molecular mechanisms that regulate FoxM1 expression remain largely unknown. In the current study, we demonstrated that tumor necrosis factor (TNF)-αα induced FoxM1 expression and transactivated its promoter activity in hepatoma cells. Serial 5" deletion and site-directed mutagenesis revealed that the induction of FoxM1 expression by TNF-α was dependent upon the hypoxia-inducible factor 1 (HIF1)-1 and HIF1-3/4 binding sites within the FoxM1 promoter. Furthermore, at the transcriptional level, the stabilization of HIF-1α via reactive oxygen species generation led to the binding of HIF-1α to the FoxM1 promoter and resulted in increased FoxM1 expression. The inhibition of both HIF-1α expression and reactive oxygen species generation significantly decreased TNF-α-induced FoxM1 overexpression. Consequently, the upregulation of FoxM1 promoted the proliferation of hepatoma cells and enhanced their resistance to TNF-α-induced apoptosis. Consistently, there was a positive correlation between HIF-1α and FoxM1 expression in 406 human hepatocellular carcinoma tissues, and the combination of these two parameters was a powerful predictor of poor prognosis in hepatocellular carcinoma patients after curative resection. Here, we report a new molecular mechanism by which FoxM1 expression is regulated by the TNF-α/reactive oxygen species/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis.
增殖特异性转录因子叉头盒 M1（FoxM1）作为癌细胞生长和存活的主调控因子，在肝细胞癌的发生发展中发挥着重要作用。然而，调节 FoxM1 表达的分子机制在很大程度上仍然未知。在本研究中，我们证明肿瘤坏死因子（TNF）-α诱导肝癌细胞中 FoxM1 的表达并反式激活其启动子活性。连续 5'缺失和定点突变显示，TNF-α诱导 FoxM1 表达依赖于 FoxM1 启动子内的缺氧诱导因子 1（HIF1）-1 和 HIF1-3/4 结合位点。此外，在转录水平上，通过活性氧生成稳定 HIF-1α，导致 HIF-1α与 FoxM1 启动子结合，从而增加 FoxM1 表达。抑制 HIF-1α 的表达和活性氧的生成显著减少 TNF-α诱导的 FoxM1 过表达。因此，FoxM1 的上调促进了肝癌细胞的增殖，并增强了它们对 TNF-α诱导的凋亡的抵抗。一致地，在 406 个人肝癌组织中观察到 HIF-1α和 FoxM1 表达之间存在正相关，并且这两个参数的组合是肝癌患者根治性切除术后预后不良的有力预测因子。在这里，我们报告了 FoxM1 表达受 TNF-α/活性氧/HIF-1 通路调节的新分子机制，该机制导致肝癌细胞的增殖及其对凋亡的抵抗。
