Bertout Jessica A, Patel Shetal A, Fryer Benjamin H, Durham Amy C, Covello Kelly L, Olive Kenneth P, Goldschmidt Michael H, Simon M Celeste
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer Res. 2009 Apr 1;69(7):3213-20. doi: 10.1158/0008-5472.CAN-08-4223. Epub 2009 Mar 17.
Hypoxia inducible factors (HIF) are critical mediators of the cellular response to decreased oxygen tension and are overexpressed in a number of tumors. Although HIF1alpha and HIF2alpha share a high degree of sequence homology, recent work has shown that the two alpha subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFalpha subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2alpha expression and Hif1alpha(+/-) mice to homozygotes for the R270H mutation in p53. Here, we report that p53(R270H/R270H) mice, which have not been previously described, develop a unique tumor spectrum relative to p53(R270H/-) mice, including a high incidence of thymic lymphomas. Heterozygosity for Hif1alpha significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1alpha levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. These observations uncover a novel role for HIF1alpha in Notch pathway activation during T-cell lymphomagenesis.
缺氧诱导因子（HIF）是细胞对氧张力降低反应的关键介质，在许多肿瘤中过度表达。尽管HIF1α和HIF2α具有高度的序列同源性，但最近的研究表明，这两个α亚基对肿瘤生长可能具有相反的组织特异性作用。为了直接比较每个HIFα亚基在自发肿瘤发生中的作用，我们将一个扩大HIF2α表达的小鼠模型和Hif1α(+/-)小鼠与p53中R270H突变的纯合子进行杂交。在此，我们报告，之前未被描述过的p53(R270H/R270H)小鼠相对于p53(R270H/-)小鼠会发展出独特的肿瘤谱，包括高发性胸腺淋巴瘤。Hif1α的杂合性显著降低了该模型中观察到的胸腺淋巴瘤的发生率。此外，Hif1α水平的降低与活化的Notch1稳定性的降低以及Notch靶基因Dtx1和Nrarp的表达减少相关。这些观察结果揭示了HIF1α在T细胞淋巴瘤发生过程中Notch途径激活中的新作用。
