Gudas Lorraine J, Fu Leiping, Minton Denise R, Mongan Nigel P, Nanus David M
Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, NY, 10065, USA,
J Mol Med (Berl). 2014 Aug;92(8):825-36. doi: 10.1007/s00109-014-1180-z. Epub 2014 Jun 12.
The transcription factor HIF1α is implicated in the development of clear cell renal cell carcinoma (ccRCC). Although HIF1α was initially believed to be essential for ccRCC development, recent studies hypothesize an oncogenic role for HIF2α in ccRCC, but a tumor suppressor role for HIF1α, leading to uncertainty as to the precise roles of the different HIF transcription factors in this disease. Using evidence available from studies with human ccRCC cell lines, mouse xenografts, murine models of ccRCC, and human ccRCC specimens, we evaluate the roles of HIF1α and HIF2α in the pathogenesis of ccRCC. We present a convergence of clinical and mechanistic data supporting an important role for HIF1α in promoting tumorigenesis in a clinically important and large subset of ccRCC. This indicates that current understanding of the exact roles of HIF1α and HIF2α is incomplete and that further research is required to determine the diverse roles of HIF1α and HIF2α in ccRCC.
The TRACK mouse ccRCC model with constitutively active HIF1α but not HIF2α expressed in proximal tubules develops RCC. HIF1α protein is expressed in the majority of human ccRCC specimens. Elevated HIF1α in ccRCC correlates with a worse prognosis. Many publications do not support a tumor suppressor role for HIF1α in ccRCC. HIF1α, but not HIF2α, is expressed in some types of cancer stem cells.
转录因子HIF1α与透明细胞肾细胞癌（ccRCC）的发生发展有关。虽然HIF1α最初被认为是ccRCC发生所必需的，但最近的研究推测HIF2α在ccRCC中具有致癌作用，而HIF1α具有肿瘤抑制作用，这导致不同的HIF转录因子在该疾病中的精确作用存在不确定性。利用来自人类ccRCC细胞系、小鼠异种移植、ccRCC小鼠模型和人类ccRCC标本的研究证据，我们评估了HIF1α和HIF2α在ccRCC发病机制中的作用。我们展示了临床和机制数据的趋同，支持HIF1α在临床上重要的ccRCC大子集中促进肿瘤发生的重要作用。这表明目前对HIF1α和HIF2α确切作用的理解是不完整的，需要进一步研究以确定HIF1α和HIF2α在ccRCC中的不同作用。
在近端小管中表达组成型活性HIF1α而非HIF2α的TRACK小鼠ccRCC模型会发生肾细胞癌。HIF1α蛋白在大多数人类ccRCC标本中表达。ccRCC中HIF1α升高与较差的预后相关。许多出版物不支持HIF1α在ccRCC中具有肿瘤抑制作用。HIF1α而非HIF2α在某些类型的癌症干细胞中表达。
