Kim Chong M, Vocke Cathy, Torres-Cabala Carlos, Yang Youfeng, Schmidt Laura, Walther McClellan, Linehan W Marston
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1107, USA.
J Urol. 2006 May;175(5):1908-14. doi: 10.1016/S0022-5347(05)00890-6.
The role of the HIF class of transcription factors has been implicated to be a critical step in clear cell kidney tumorigenesis. To assess if HIF over expression is a prominent feature of other renal cell carcinoma histological subtypes we characterized the expression of HIF-1alpha and HIF-2alpha in genetically distinct early renal cortical tumors.
Nascent renal tumors of distinct histology from patients with a hereditary renal tumor syndrome were characterized for HIF expression using high amplification immunohistochemistry. In addition, indirect immunofluorescence and confocal microscopy were used for subcellular localization of HIF-1alpha and 2alpha in clear cell renal carcinoma cells.
Clear cell RCC tumors from patients with von Hippel-Lindau disease strongly expressed HIF-1alpha and HIF-2alpha (10 of 12 and 12 of 12 tumors, respectively). Chromophobe tumors from patients with Birt-Hogg-Dubé syndrome expressed predominantly HIF-2alpha with weaker HIF-1alpha expression (12 of 12 and 6 of 12 tumors, respectively). Consistent HIF-1alpha expression was not seen in type I papillary tumors from patients with hereditary papillary renal carcinoma (3 of 12 tumors). However, half of the type I papillary tumors (6 of 12) expressed HIF-2alpha.
Differential patterns of HIF-1alpha and HIF-2alpha protein over expression were found among the 3 human kidney tumor types associated with multifocal hereditary kidney tumor syndromes. Consistent, simultaneous over expression of HIF-1alpha and HIF-2alpha appears to be specific to VHL negative clear cell renal cell carcinoma. Consistent HIF-2alpha expression was found in all 3 renal cortical tumor subtypes, suggesting a pivotal role in renal cortical tumorigenesis. Differential function of HIF-1alpha vs HIF-2alpha is suggested by the distinct subcellular localization pattern of HIF-1alpha and HIF-2alpha in clear cell renal carcinoma cells.
转录因子HIF家族的作用被认为是透明细胞肾肿瘤发生过程中的关键步骤。为了评估HIF过表达是否是其他肾细胞癌组织学亚型的显著特征，我们对基因不同的早期肾皮质肿瘤中HIF-1α和HIF-2α的表达进行了表征。
使用高放大免疫组织化学对患有遗传性肾肿瘤综合征患者的不同组织学类型的新生肾肿瘤进行HIF表达特征分析。此外，间接免疫荧光和共聚焦显微镜用于在透明细胞肾癌细胞中对HIF-1α和2α进行亚细胞定位。
患有冯·希佩尔-林道病患者的透明细胞肾细胞癌肿瘤强烈表达HIF-1α和HIF-2α（分别为12个肿瘤中的10个和12个肿瘤中的12个）。患有Birt-Hogg-Dubé综合征患者的嫌色细胞瘤主要表达HIF-2α，HIF-1α表达较弱（分别为12个肿瘤中的12个和12个肿瘤中的6个）。在遗传性乳头状肾细胞癌患者的I型乳头状肿瘤中未观察到一致的HIF-1α表达（12个肿瘤中的3个）。然而，一半的I型乳头状肿瘤（12个中的6个）表达HIF-2α。
在与多灶性遗传性肾肿瘤综合征相关的3种人类肾肿瘤类型中发现了HIF-1α和HIF-2α蛋白过表达的差异模式。HIF-1α和HIF-2α的一致、同时过表达似乎是VHL阴性透明细胞肾细胞癌所特有的。在所有3种肾皮质肿瘤亚型中均发现了一致的HIF-2α表达，表明其在肾皮质肿瘤发生中起关键作用。透明细胞肾癌细胞中HIF-1α和HIF-2α不同的亚细胞定位模式提示了HIF-1α与HIF-2α的功能差异。
