Gordan John D, Lal Priti, Dondeti Vijay R, Letrero Richard, Parekh Krishna N, Oquendo C Elisa, Greenberg Roger A, Flaherty Keith T, Rathmell W Kimryn, Keith Brian, Simon M Celeste, Nathanson Katherine L
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Cancer Cell. 2008 Dec 9;14(6):435-46. doi: 10.1016/j.ccr.2008.10.016.
von Hippel-Lindau (VHL) tumor suppressor loss results in hypoxia-inducible factor alpha (HIF-alpha) stabilization and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1alpha and HIF-2alpha on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-alpha expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient HIF-1alpha/HIF-2alpha-expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2alpha displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-alpha effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies.
冯·希佩尔-林道（VHL）肿瘤抑制因子缺失会导致缺氧诱导因子α（HIF-α）稳定，且在70%的散发性透明细胞肾细胞癌（ccRCC）中出现。为了确定HIF-1α和HIF-2α对c-Myc活性的相反影响是否调节人类ccRCC进展，我们分析了160例原发性肿瘤中的VHL基因型和HIF-α表达，这些肿瘤分为具有不同分子特征的三组。有趣的是，VHL完整的ccRCC以及表达pVHL缺陷型HIF-1α/HIF-2α的ccRCC表现出增强的Akt/mTOR和ERK/MAPK信号传导。相比之下，仅表达HIF-2α的pVHL缺陷型ccRCC显示出c-Myc活性升高，导致增殖增强和对复制应激的抗性增强。ccRCC行为中这些可重复的差异描绘了HIF-α在体内对c-Myc的影响，并为选择靶向治疗提供了分子标准。
