HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice
HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice
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DOI：
10.1038/s41467-020-17873-3
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发表时间：
2020-08-17
影响因子：
16.6
通讯作者：
Frew, Ian J.
中科院分区：
文献类型：
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作者：
Hoefflin, Rouven;Harlander, Sabine;Frew, Ian J.
VHL的突变失活是大多数透明细胞肾细胞癌（ccRCC）中最早的遗传事件，导致HIF-1 α和HIF-2 α转录因子的积累。虽然人ccRCC的相关研究和使用人ccRCC细胞系的功能研究已经暗示HIF-1 α作为侵袭性肿瘤行为的抑制剂，HIF-2 α作为侵袭性肿瘤行为的促进剂，但它们在肿瘤发病中的作用尚未在功能上得到解决。在本文中，我们使用一个本地ccRCC模型表明，Hif 1a是肿瘤形成所必需的，而Hif 2a缺失对肿瘤的发生和生长只有很小的影响。透明细胞表型需要HIF-1 α和HIF-2 α。转录组学和蛋白质组学分析显示，HIF-1 α调节糖酵解，而HIF-2 α调节与脂蛋白代谢、核糖体生物合成以及E2 F和MYC转录活性相关的基因。HIF-2 α缺陷型肿瘤的特征是抗原呈递、干扰素信号传导和CD 8（+）T细胞浸润和活化增加。HIF 1A单拷贝丢失或HIF 2A mRNA高水平表达与人ccRCC中免疫微环境改变相关。这些研究揭示了HIF-1 α在ccRCC启动中的致癌作用，并表明HIF-1 α和HIF-2 α活性平衡的改变可以影响ccRCC生物学和疾病侵袭性的不同方面。VHL的基因失活导致HIF-1 α/HIF-2 α的稳定，并与肾透明细胞癌（ccRCC）的发生和进展相关。使用具有Vhl缺失的ccRCC的本地小鼠模型，在这里，作者表明HIF-1 α是肿瘤形成所必需的，而HIF-2 α缺失仅具有中等影响。
Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1 alpha and HIF-2 alpha transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1 alpha as an inhibitor and HIF-2 alpha as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1 alpha and HIF-2 alpha are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1 alpha regulates glycolysis while HIF-2 alpha regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2 alpha -deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8(+) T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1 alpha in ccRCC initiation and suggest that alterations in the balance of HIF-1 alpha and HIF-2 alpha activities can affect different aspects of ccRCC biology and disease aggressiveness. Genetic inactivation of VHL leads to stabilization of HIF-1 alpha /HIF-2 alpha and is associated with clear cell renal cell carcinoma (ccRCC) initiation and progression. Using an autochthonous mouse model of ccRCC with Vhl deletion, here the authors show that HIF-1 alpha is necessary for tumor formation, while HIF-2 alpha deletion has only a moderate effect.