Jensen Randy L, Gillespie David, House Paul, Layfield Lester, Shelton Clough
Department of Neurosurgery, University of Utah, Salt Lake City, Utah 84132-2303, USA.
J Neurosurg. 2004 Mar;100(3):488-97. doi: 10.3171/jns.2004.100.3.0488.
Endolymphatic sac (ELS) tumors are low-grade malignancies of the temporal bone that are associated with von Hippel-Lindau (VHL) disease but can also occur sporadically. The VHL gene product VHL protein is important in the regulation of hypoxia inducible factor (HIF)-1alpha, which controls expression of molecules that are important in angiogenesis and cell metabolism. In this study the authors examine the role of VHL and HIF-1 in ELS tumors.
The ELS tumors from three patients were examined using the following method: DNA from tumor tissue was isolated, amplified by polymerase chain reaction and the VHL gene sequence was compared with the known wild-type sequence. Loss of heterozygosity (LOH) studies were performed to confirm the sequencing data. Immunohistochemical evaluation for VHL, HIF-1alpha, vascular endothelial growth factor (VEGF), and carbonic anhydrase IX (CA IX) was performed. Snap-frozen tumor tissue was examined using Western blot and HIF-1 immunoassays for HIF-1alpha and VHL expression. Two patients had sporadic ELS tumors and the other one suffered from VHL disease. Results of VHL gene sequencing were normal in the tissue derived from the sporadic ELS tumors. The ELS tumor, pheochromocytoma, and spinal hemangioblastoma were heterozygous for the same C-to-A transversion found in the germline carried by the patient with VHL disease. No LOH was detected in the tumor tissue obtained in the patient with VHL disease. Expression of HIF-1alpha, VEGF, and CA IX evaluated using immunohistochemical studies was elevated in the VHL-associated tumors. Nevertheless, Western blots and immunoassays for HIF-1alpha did not show elevated expression in these tumors.
The sporadic and VHL disease-associated ELS tumors in this study had normal VHL-mediated HIF-1 regulation. This is a result of normal VHL gene expression in the case of the sporadic ELS tumor. In the VHL-associated ELS tumor, this is due to one normal copy of the VHL gene and adequate VHL gene expression.
内淋巴囊（ELS）肿瘤是颞骨的低级别恶性肿瘤，与冯·希佩尔－林道（VHL）病相关，但也可散发发生。VHL基因产物VHL蛋白在缺氧诱导因子（HIF）-1α的调节中起重要作用，HIF-1α控制着在血管生成和细胞代谢中起重要作用的分子的表达。在本研究中，作者探讨了VHL和HIF-1在ELS肿瘤中的作用。
采用以下方法检查3例患者的ELS肿瘤：从肿瘤组织中分离DNA，通过聚合酶链反应进行扩增，并将VHL基因序列与已知的野生型序列进行比较。进行杂合性缺失（LOH）研究以确认测序数据。对VHL、HIF-1α、血管内皮生长因子（VEGF）和碳酸酐酶IX（CA IX）进行免疫组织化学评估。使用蛋白质免疫印迹法和HIF-1免疫测定法检测速冻肿瘤组织中HIF-1α和VHL的表达。2例患者患有散发的ELS肿瘤，另1例患有VHL病。散发ELS肿瘤组织的VHL基因测序结果正常。ELS肿瘤、嗜铬细胞瘤和脊髓血管母细胞瘤与VHL病患者种系中发现的相同的C到A颠换呈杂合状态。在VHL病患者获得的肿瘤组织中未检测到LOH。使用免疫组织化学研究评估的HIF-1α、VEGF和CA IX的表达在与VHL相关的肿瘤中升高。然而，蛋白质免疫印迹法和HIF-1α免疫测定法并未显示这些肿瘤中表达升高。
本研究中散发的和与VHL病相关的ELS肿瘤具有正常的VHL介导的HIF-1调节。对于散发的ELS肿瘤，这是VHL基因正常表达的结果。在与VHL相关的ELS肿瘤中，这是由于VHL基因的一个正常拷贝和足够的VHL基因表达。
