Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer.
Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer.
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DOI：
10.1016/j.eururo.2015.08.007
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发表时间：
2016-04
期刊：
影响因子：
23.4
通讯作者：
Mole, David R.
中科院分区：
文献类型：
--
作者：
Schoedel, Johannes;Grampp, Steffen;Maher, Eamonn R.;Moch, Holger;Ratcliffe, Peter J.;Russo, Paul;Mole, David R.
关键词：
肾癌是一种常见的泌尿系统恶性肿瘤，转移性疾病的治疗选择有限。大多数透明细胞肾细胞癌（ccRCC）与von Hippel-Lindau肿瘤抑制因子（pVHL）功能丧失和缺氧通路失调相关。本文综述了近年来从遗传学和生物学研究中发现的低氧及低氧相关通路在肾癌发生发展中的重要作用。我们使用缺氧、缺氧诱导因子、肾癌和VHL等关键词进行系统性检索。肿瘤抑制因子pVHL的鉴定允许表征重要的ccRCC相关途径。pVHL靶向低氧诱导转录因子（HIF）的α亚基用于蛋白酶体降解。两种主要的HIF-α亚型对RCC生物学具有相反的作用，可能是通过与其他癌基因的不同相互作用。此外，HIF-1α活性通常因ccRCC中的染色体缺失而降低，并且HIF-1活性增加可降低异种移植肿瘤模型中的肿瘤负荷。相反，HIF-2α基因位点的多态性易患ccRCC，HIF-2α促进肿瘤生长。遗传学研究已经揭示了染色质修饰酶基因在ccRCC中的突出作用，并且这些可能进一步调节HIF应答的特定方面。这表明，不是HIF的整体激活，而是反应的特定组分在促进肾癌中很重要。这些过程中的一些已经是目前治疗策略的目标，对这一途径的进一步研究可能会产生治疗RCC的新方法。与许多肿瘤类型不同，HIF-1α和HIF-2α在ccRCC生物学中具有相反的作用，HIF-1α作为肿瘤抑制因子，HIF-2α作为癌基因。VHL失活的总体效果将取决于HIF反应的微调。高水平的低氧诱导转录因子（HIF）在肾透明细胞型癌中特别重要，在这种癌中它们不再受到von Hippel-Lindau蛋白的适当调节。这两种HIF-α蛋白对肿瘤演变具有相反的作用。
Renal cancer is a common urologic malignancy, and therapeutic options for metastatic disease are limited. Most clear cell renal cell carcinomas (ccRCC) are associated with loss of von Hippel-Lindau tumor suppressor (pVHL) function and deregulation of hypoxia pathways. This review summarizes recent evidence from genetic and biological studies showing that hypoxia and hypoxia-related pathways play critical roles in the development and progress of renal cancer. We used a systematic search for articles using the keywords hypoxia, HIF, renal cancer, and VHL. Identification of the tumor suppressor pVHL has allowed the characterization of important ccRCC-associated pathways. pVHL targets α-subunits of hypoxia-inducible transcription factors (HIF) for proteasomal degradation. The two main HIF-α isoforms have opposing effects on RCC biology, possibly through distinct interactions with additional oncogenes. Furthermore, HIF-1α activity is commonly diminished by chromosomal deletion in ccRCCs, and increased HIF-1 activity reduces tumor burden in xenograft tumor models. Conversely, polymorphisms at the HIF-2α gene locus predispose to the development of ccRCCs, and HIF-2α promotes tumor growth. Genetic studies have revealed a prominent role for chromatin-modifying enzyme genes in ccRCC, and these may further modulate specific aspects of the HIF response. This suggests that, rather than global activation of HIF, specific components of the response are important in promoting kidney cancer. Some of these processes are already targets for current therapeutic strategies, and further dissection of this pathway might yield novel methods of treating RCC. In contrast to many tumor types, HIF-1α and HIF-2α have opposing effects in ccRCC biology, with HIF-1α acting as a tumor suppressor and HIF-2α acting as an oncogene. The overall effect of VHL inactivation will depend on fine-tuning of the HIF response. High levels of hypoxia-inducible transcription factors (HIF) are particularly important in the clear cell type of kidney cancer, in which they are no longer properly regulated by the von Hippel-Lindau protein. The two HIF-α proteins have opposing effects on tumor evolution.
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DOI：
10.1158/1078-0432.ccr-13-0491
发表时间：
2013-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Choueiri TK;Fay AP;Gagnon R;Lin Y;Bahamon B;Brown V;Rosenberg JE;Hutson TE;Baker-Neblett KL;Carpenter C;Liu Y;Pandite L;Signoretti S
通讯作者：
Signoretti S
影响因子：
6.6
作者：
Choueiri, Toni K.;Vaziri, Susan A. J.;Ganapathi, Ram
通讯作者：
Ganapathi, Ram
影响因子：
4.8
作者：
Cockman, ME;Masson, N;Maxwell, PH
通讯作者：
Maxwell, PH
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
DUAN, DR;PAUSE, A;KLAUSNER, RD
通讯作者：
KLAUSNER, RD