Michaylira Carmen Z, Nakagawa Hiroshi
Gastroenterology Division, Department of Medicine, Abramson Cancer Center and Family Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer Biol Ther. 2006 May;5(5):476-9. doi: 10.4161/cbt.5.5.2749. Epub 2006 May 26.
Hypoxia-inducible factor (HIF)-1alpha, a global regulator of oxygen homeostasis, plays a crucial role in tumor cell adaptation to the hypoxic microenvironment through transcriptional regulation of its target genes. These genes in turn are involved in a plethora of biochemical as well as cell biological processes, including glucose metabolism, apoptosis and angiogenesis. In melanoma, HIF-1alpha has been implicated in tumor progression with effects upon metastasis and angiogenesis. However, its role in malignant transformation by oncogenes has not been described. Bedogni et al. (Cancer Cell 2005, 8:443-54) report that the hypoxic microenvironment in the skin contributes to melanocyte transformation and tumor growth induced by oncogenes Ras and Akt, which are frequently activated in melanoma. HIF-1alpha activity was found to be required in Akt-induced melanocyte transformation and tumor growth and it was suppressed greatly by mTOR inhibition with rapamycin. Since mTOR regulates HIF-1alpha expression and its transcriptional activity, rapamycin was proposed as a promising hypoxia-related therapeutic approach in melanoma treatment. This study sheds light upon the role of HIF-1alpha in the early stage of melanoma development and highlights the importance of the Akt-mTOR pathway in the regulation of HIF-1alpha.
缺氧诱导因子（HIF）-1α是氧稳态的全局调节因子，通过对其靶基因的转录调控，在肿瘤细胞适应缺氧微环境中发挥关键作用。这些基因进而参与大量生化以及细胞生物学过程，包括葡萄糖代谢、细胞凋亡和血管生成。在黑色素瘤中，HIF-1α与肿瘤进展有关，对转移和血管生成有影响。然而，其在癌基因介导的恶性转化中的作用尚未见报道。贝多尼等人（《癌细胞》2005年，第8卷：443 - 54页）报告称，皮肤中的缺氧微环境有助于癌基因Ras和Akt诱导的黑素细胞转化和肿瘤生长，而这两种癌基因在黑色素瘤中经常被激活。研究发现，Akt诱导的黑素细胞转化和肿瘤生长需要HIF-1α的活性，并且雷帕霉素抑制mTOR可大大抑制HIF-1α的活性。由于mTOR调节HIF-1α的表达及其转录活性，因此有人提出雷帕霉素有望成为黑色素瘤治疗中一种与缺氧相关的治疗方法。这项研究揭示了HIF-1α在黑色素瘤发展早期的作用，并突出了Akt-mTOR途径在调节HIF-1α中的重要性。
