Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, No. 8 Xishiku Street, Xicheng, Beijing, P.R. China.
Int J Mol Med. 2010 Dec;26(6):907-12. doi: 10.3892/ijmm_00000541.
Decreased levels of von Hippel-Lindau (VHL) tumour suppressor protein are associated with up-regulation of hypoxia-inducible factor (HIF), leading to increased tumour proliferation, angiogenesis and progression. The role of erythropoietin (EPO), a target gene for HIF, remains unknown for sporadic clear cell renal cell carcinoma (sCCRCC). In this study, we determined expression levels of EPO, and its correlation with VHL mutations and HIF-1α and HIF-2α expression in 82 patients identified with sCCRCC following nephrectomy. We identified VHL gene alterations using multiplex polymerase chain reaction, purifying products of polymerase chain reaction, and direct sequencing. Immunohistochemical staining for HIF-1α, HIF-2α and EPO was performed for tumour and corresponding normal tissues. Data were analyzed with respect to clinicopathological factors. EPO was detected in 87.8% of sCCRCC tumours versus 7.3% for normal tissues. EPO expression was related to tumours demonstrating VHL gene abnormalities. Of specimens with VHL alterations 95.6% tested positive for EPO, versus 78.3% when VHL gene expression was normal (P<0.01). EPO was identified in 96.2 and 94.2% of HIF-1α and HIF-2α positive specimens, respectively, compared to 72.4 and 53.8% for HIF-1α and HIF-2α negative groups (p<0.01). Moreover, EPO expression correlated significantly with increasing nuclear grade (p<0.05). HIF-2α was identified in 84.1% of sCCRCC, compared to 64.6% for HIF-1α. Expression of HIF-1α, HIF-2α and EPO is common in sCCRCC. Although both forms of HIF up-regulate expression of EPO, the relationship to HIF-2α appears to be more pronounced. The VHL-HIF-EPO pathway requires further study, as it may represent a potential molecular target for therapy of sCCRCC.
抑瘤素 D（VHL）肿瘤抑制蛋白水平降低与低氧诱导因子（HIF）的上调有关，导致肿瘤增殖、血管生成和进展增加。促红细胞生成素（EPO）是 HIF 的靶基因，其在散发性透明细胞肾细胞癌（sCCRCC）中的作用尚不清楚。在这项研究中，我们通过肾切除术确定了 82 例 sCCRCC 患者肿瘤中 EPO 的表达水平，并确定了其与 VHL 基因突变和 HIF-1α 和 HIF-2α表达的相关性。我们使用多重聚合酶链反应、聚合酶链反应产物纯化和直接测序来鉴定 VHL 基因改变。对肿瘤和相应正常组织进行 HIF-1α、HIF-2α 和 EPO 的免疫组织化学染色。根据临床病理因素对数据进行分析。在 87.8%的 sCCRCC 肿瘤中检测到 EPO，而在正常组织中为 7.3%。EPO 的表达与显示 VHL 基因异常的肿瘤有关。在 VHL 改变的标本中，95.6%的标本 EPO 检测阳性，而 VHL 基因表达正常的标本为 78.3%（P<0.01）。EPO 在 HIF-1α 和 HIF-2α 阳性标本中的检出率分别为 96.2%和 94.2%，而在 HIF-1α 和 HIF-2α 阴性组中分别为 72.4%和 53.8%（p<0.01）。此外，EPO 的表达与核分级的增加显著相关（p<0.05）。在 sCCRCC 中检测到 84.1%的 HIF-2α，而在 HIF-1α 中为 64.6%。HIF-1α、HIF-2α 和 EPO 的表达在 sCCRCC 中很常见。尽管两种形式的 HIF 都上调 EPO 的表达，但与 HIF-2α 的关系似乎更为明显。VHL-HIF-EPO 途径需要进一步研究，因为它可能代表 sCCRCC 治疗的潜在分子靶点。
