VHL 基因突变在 CCRCC 中并不决定 HIF、CAIX、hnRNP A2/B1 和骨桥蛋白的失调。

VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.

机构信息

Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork, Ireland.

出版信息

Cell Oncol (Dordr). 2011 Jun;34(3):225-34. doi: 10.1007/s13402-011-0029-5. Epub 2011 May 6.

DOI:10.1007/s13402-011-0029-5

PMID:21547579

Abstract

BACKGROUND

Von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-α (HIF-α), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP)A2/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue.

METHODS

The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by Real-Time RT-PCR. Expression of pVHL's protein targets were determined by Western blotting in 17 paired patient samples.

RESULTS

VHL genetic alterations were identified in 43.5% (10/23) of CCRCCs. HIF-1α, HIF-2α and CAIX were up-regulated in 88.2% (15/17), 100% (17/17) and 88.2% (15/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status.

CONCLUSION

As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), this data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

摘要

背景

冯·希佩尔-林道（VHL）肿瘤抑制基因失活与肾透明细胞癌（CCRCC）的发生有关。VHL 蛋白（pVHL）被认为可以调节多种蛋白的表达，包括缺氧诱导因子-α（HIF-α）、碳酸酐酶（CA）IX、异质核核糖核蛋白（hnRNP）A2/B1 和骨桥蛋白。虽然已经在体外对 pVHL 进行了表征，但临床研究有限。我们评估了 VHL 基因突变对配对正常和肿瘤组织中几种 pVHL 蛋白靶标表达的影响。

方法

对 23 例 CCRCC 患者进行了 VHL 基因测序，并通过实时 RT-PCR 评估了 VHL 转录水平。在 17 对配对患者样本中通过 Western blot 检测了 pVHL 蛋白靶标的表达。

结果

在 43.5%（10/23）的 CCRCC 中发现了 VHL 基因突变。HIF-1α、HIF-2α 和 CAIX 在 88.2%（15/17）、100%（17/17）和 88.2%（15/17）的肿瘤中上调，其表达独立于 VHL 状态。hnRNP A2/B1 和骨桥蛋白在 CCRCC 中的表达是可变的，与 VHL 遗传状态无关。