Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
J Oncol. 2010;2010:757908. doi: 10.1155/2010/757908. Epub 2010 Jun 27.
In cultured clear-cell renal carcinoma (CCRCC) 786-0 cells transfected with HIF1alpha (HIF-1+), HIF-2alpha (HIF-2+), or empty vector (EV), no significant differences were observed in the growth rates in vitro, but when grown in vivo as xenografts HIF-2alpha significantly increased, and HIF-1alpha significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2alpha in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype.
在转染了 HIF1alpha（HIF-1+）、HIF-2alpha（HIF-2+）或空载体（EV）的培养的透明细胞肾细胞癌（CCRCC）786-0 细胞中，体外生长速率没有观察到显著差异，但当作为异种移植物在体内生长时，与 EV 肿瘤相比，HIF-2alpha 显著增加，而 HIF-1alpha 显著降低生长速率。与增殖相关的因素在 HIF-2+肿瘤中增加，与细胞死亡相关的因素减少。代谢物谱显示 HIF-2+肿瘤中的葡萄糖水平较高，而乳酸和丙氨酸水平较低，而免疫染色显示与对照肿瘤相比，丙酮酸脱氢酶较高，而丙酮酸脱氢酶激酶 1 较低。总之，这些结果表明，HIF-2alpha 在 CCRCC 786-0 肿瘤中的过表达通过维持低水平的糖酵解和允许更多的线粒体代谢以及对 ROS 诱导的 DNA 损伤的耐受性来调节肿瘤的生长。观察到的生长曲线可能是通过对更氧化表型的适应性变化来介导的。
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