Hypoxia-inducible factor 1α is essential for hypoxic p27 induction in endometrioid endometrial carcinoma
Hypoxia-inducible factor 1α is essential for hypoxic p27 induction in endometrioid endometrial carcinoma
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DOI：
10.1002/path.2244
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发表时间：
2008-01-01
影响因子：
7.3
通讯作者：
van Diest, P. J.
中科院分区：
文献类型：
--
作者：
Horree, N.;Gort, E. H.;van Diest, P. J.
缺氧诱导因子（HIF-1α）在细胞对缺氧的适应性反应中发挥着重要作用。细胞周期蛋白依赖性激酶抑制剂p27(Kip1)在正常子宫内膜中高表达，但在子宫内膜癌变过程中丢失。然而，在高级癌症中，观察到 p27 重新表达。我们分析了 HIF-1 α 在子宫内膜癌体内和体外缺氧诱导的 p27 表达中的作用。对子宫内膜样子宫内膜癌 (n = 39) 的石蜡包埋标本进行 HIF-1 α、p27 和 Ki67 的免疫组织化学染色。 HEC1B 是一种子宫内膜癌细胞系，在存在或不存在瞬时表达的靶向 HIF-1 α 的短发夹 RNA 的情况下，在常氧或低氧条件下培养。通过蛋白质印迹评估 p27 和 HIF-1 α 的蛋白表达。免疫组织化学染色显示，67% 的病例中有坏死周围 HIF-1 α 表达，46% 的病例中 p27 染色集中在肿瘤岛中央，主要在坏死周围。在 50% 具有坏死周围 HIF-1 α 表达的肿瘤中，观察到 p27 和 HIF-1 α 坏死周围/中央共定位。在这些肿瘤切片中，缺氧相关的 p27 表达显示坏死周围增殖较少。对培养的子宫内膜癌细胞的分析表明，p27 蛋白表达是由缺氧诱导的。使用 RNAi 短暂敲除 HIF-1 α 可消除这种诱导作用。此外，缺氧诱导 HEC1B 细胞的细胞周期停滞。我们的结论是，在子宫内膜样子宫内膜癌中，缺氧导致的 p27 重新表达是 HIF-1 α 依赖性的，并导致细胞周期停滞。这可能有助于肿瘤缺氧部分的癌细胞存活。版权所有 (c) 2007 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
Hypoxia-inducible factor lot (HIF-1 alpha) plays an essential role in the adaptive response of cells to hypoxia. The cyclin-dependent kinase inhibitor p27(Kip1) is highly expressed in the normal endometrium but is lost during endometrial carcinogenesis. However, in high-grade cancers, p27 re-expression is observed. We analysed the role of HIF-1 alpha in hypoxia-induced expression of p27 in vitro and in vivo in endometrial cancer. Paraffin-embedded specimens from endometrioid endometrial carcinoma (n=39) were stained immunohistochemically for HIF-1 alpha, p27, and Ki67. HEC1B, an endometrial carcinoma cell line, was cultured under normoxic or hypoxic conditions in the presence or absence of transiently expressed short hairpin RNAs targeting HIF-1 alpha. Protein expression of p27 and HIF-1 alpha was assessed by western blotting. Immunohistochemical staining revealed perinecrotic HIF-1 alpha expression in 67% of the cases and p27 staining centrally in the tumour islands, mostly around necrosis, in 46% of the cases. In 50% of the tumours with perinecrotic HIF-1 alpha expression, p27 and HIF-1 alpha perinecrotic/central co-localization was observed. In these tumour sections, hypoxia-associated p27 expression showed less proliferation around necrosis. Analysis of cultured endometrial carcinoma cells demonstrated that p27 protein expression is induced by hypoxia. This induction was abrogated by transient knockdown of HIF-1 alpha using RNAi Furthermore, hypoxia induced cell cycle arrest in HEC1B cells. We conclude that, in endometrioid endometrial carcinoma, p27 re-expression by hypoxia is HIF-1 alpha-dependent and leads to cell cycle arrest. This may contribute to the survival of cancer cells in hypoxic parts of the tumour. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.