Hypoxia-inducible factor-1alpha suppresses squamous carcinogenic progression and epithelial-mesenchymal transition.
Hypoxia-inducible factor-1alpha suppresses squamous carcinogenic progression and epithelial-mesenchymal transition.
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DOI：
10.1158/0008-5472.can-08-3643
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Arbeit JM
中科院分区：
文献类型：
--
作者：
Scortegagna M;Martin RJ;Kladney RD;Neumann RG;Arbeit JM
缺氧诱导因子-1是一种已知的癌症进展因子，促进生长、扩散和转移。然而，在选定的情况下，HIF-1是协调缺氧细胞周期抑制和凋亡的肿瘤抑制因子。以往的研究主要集中在HIF-1在已确定的恶性肿瘤中的功能，但对其在从肿瘤诱导到恶性肿瘤的整个癌变过程中的作用知之甚少。我们在K14-HIF-1α Pro402 A564 G（K14-HIF-1α Pro）转基因小鼠中检测了多阶段小鼠皮肤化学致癌过程中HIF-1功能的获得。转基因乳头状瘤出现更早，数量更多，每只小鼠6±3个转基因乳头状瘤，而非转基因乳头状瘤为2±1.5个，但它们分化程度更高，增殖能力更低，恶性转化受到严重抑制，转基因小鼠为7%，非转基因小鼠为40%。此外，转基因癌症维持鳞状分化，而上皮间质转化是常见的非转基因恶性肿瘤。转基因基底角质形成细胞上调HIF-1靶向N-myc下游调节基因-1，一种已知的人类恶性肿瘤的肿瘤抑制基因，其表达在转基因乳头状瘤和癌症中得以维持。我们还发现了一个新的HIF-1靶基因，硒结合蛋白-1（selenbp 1），一个功能未知的基因，其表达在人类癌症中丢失。因此，HIF-1可以通过反式激活基因发挥肿瘤抑制因子的作用，这些基因本身就是人类癌症中负选择的靶点。
Hypoxia-inducible factor-1 is a known cancer progression factor, promoting growth, spread, and metastasis. However, in selected contexts HIF-1 is a tumor suppressor coordinating hypoxic cell cycle suppression and apoptosis. Prior studies focused on HIF-1 function in established malignancy, however little is known about its role during the entire process of carcinogenesis from neoplasia induction to malignancy. Here we tested HIF-1 gain of function during multistage murine skin chemical carcinogenesis in K14-HIF-1αPro402A564G (K14-HIF-1αDPM) transgenic mice. Transgenic papillomas appeared earlier and were more numerous, 6±3 transgenic versus 2±1.5 nontransgenic papillomas per mouse, yet they were more differentiated, their proliferation was lower, and their malignant conversion was profoundly inhibited, 7% in transgenic versus 40% in non transgenic mice. Moreover, transgenic cancers maintained squamous differentiation whereas epithelial mesenchymal transformation was frequent in nontransgenic malignancies. Transgenic basal keratinocytes upregulated the HIF-1 target N-myc downstream regulated gene-1, a known tumor suppressor gene in human malignancy, and its expression was maintained in transgenic papillomas and cancer. We also discovered a novel HIF-1 target gene, selenium binding protein-1 (selenbp1), a gene of unknown function whose expression is lost in human cancer. Thus, HIF-1 can function as a tumor suppressor through transactivation of genes that are themselves targets for negative selection in human cancers.