Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness
Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness
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DOI：
10.1158/1078-0432.ccr-05-2022
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发表时间：
2006-02-15
影响因子：
11.5
通讯作者：
Jaakkola, PM
中科院分区：
文献类型：
--
作者：
Jokilehto, T;Rantanen, K;Jaakkola, PM
目的：肿瘤缺氧与预后不良及治疗抵抗有关。缺氧的结果在很大程度上受缺氧诱导因子（HIF-1 α和HIF-2 α）的调控。hfs反过来又受到脯氨酸羟化酶家族（PHD1-3）的负调控。PHD2亚型是常氧和轻度缺氧条件下hfs的主要下调因子。本研究旨在分析PHD2的表达和亚细胞定位与人肿瘤病理特征及HIF-1 α表达的相关性。实验设计：采用免疫组化方法研究正常石蜡包埋组织（n = 21）和头颈部鳞状细胞癌（HNSCC; n = 44）中PHD2的表达。进一步的研究包括从HNSCC标本中检测PHD2 mRNA和HIF-1 α免疫组织化学，以及从HNSCC衍生细胞系中检测PHD2免疫细胞化学。结果：在非癌组织中，内皮细胞强烈表达PHD2。在上皮中，基底增殖层也表现出强烈的表达，而分化程度较高的上皮很少或不表达PHD2。在HNSCC中，PHD2在mRNA和蛋白水平上的表达均明显升高。此外，PHD2在分化程度较低的表型中表达增加，并部分从细胞质重新定位到细胞核。内源性高核PHD2见于hnscc衍生细胞系的一个亚群。最后，虽然大多数PHD2高表达的肿瘤区域显示HIF-1 α下调，但可以检测到HIF-1 α和PHD2同时表达的区域。结论：我们的研究结果表明，细胞氧传感器PHD2水平的升高和核易位与低分化和强增殖的肿瘤有关。此外，他们暗示，在某些肿瘤中，即使PHD2水平升高也不足以下调HIF-1 α。
Purpose: Hypoxia in tumors is associated with poor prognosis and resistance to treatment. The outcome of hypoxia is largely regulated by the hypoxia-inducible factors (HIF-1 alpha and HIF-2 alpha). HIFs in turn are negatively regulated by a family of prolyl hydroxylases (PHD1-3). The PHD2 isoform is the main down-regulator of HIFs in normoxia and mild hypoxia. This study was designed to analyze the correlation of the expression and subcellular localization of PHD2 with the pathologic features of human carcinomas and HIF-1 alpha expression.Experimental Design: The expression of PHD2 was studied from paraffin-embedded normal tissue (n = 21) and head and neck squamous cell carcinoma (HNSCC; n = 44) by immunohistochemistry. Further studies included PHD2 mRNA detection and HIF-1 alpha immunohistochemistry from HNSCC specimens as well as PHD2 immunocytochemistry from HNSCC-derived cell lines.Results: In noncancerous tissue, PHD2 is robustly expressed by endothelial cells. In epithelium, the basal proliferating layer also shows strong expression, whereas the more differentiated epithelium shows little or no PHD2 expression. In HNSCC, PHD2 shows strongly elevated expression both at the mRNA and protein level. Moreover, PHD2 expression increases in less differentiated phenotypes and partially relocalizes from the cytoplasm into the nucleus. Endogenously high nuclear PHD2 is seen in a subset of HNSCC-derived cell lines. Finally, although most of the tumor regions with high PHD2 expression show down-regulated HIF-1 alpha, regions with simultaneous HIF-1 alpha and PHD2 expression could be detected.Conclusions: Our results show that increased levels and nuclear translocation of the cellular oxygen sensor, PHD2, are associated with less differentiated and strongly proliferating tumors. Furthermore, they imply that even the elevated PHD2 levels are not sufficient to down-regulate HIF-1 alpha in some tumors.