Hypoxia responsiveness in renal cell carcinoma

近年来，针对低氧诱导因子（HIF）介导的低氧诱导基因通路的研究已成为肾细胞癌（RCC）治疗的研究热点。在HIF诱导的多种基因中，血管内皮生长因子（VEGF）是血管生成、肿瘤生长和转移的关键介质之一。然而，迄今为止，关于HIF亚基（即HIF-1α和HIF-2α）之间VEGF转录的功能差异的信息有限。9株细胞中有4株VHL基因失活，原因为移码突变或甲基化。VHL基因激活的4个细胞系均存在HIF-1α表达缺失或缺失。在9个细胞系中的5个中观察到转录沉默，伴随异常CpG岛启动子区域甲基化或截短的mRNA表达，这导致野生型HIF-1α蛋白表达缺失。蛋白质表达的降低是由于mRNA表达水平低。因此，作为一个整体，蛋白质表达与mRNA表达相关。在HIF-1α表达缺失的细胞系中，VEGF表达通过HIF-2α表达维持。事实上，缺乏HIF-1α和HIF-2α的769 P细胞具有低VEGF表达。在这些HIF-1α缺陷细胞系中，HIF-2α基因的敲低表明HIF-2α调节VEGF的产生，而与VHL基因突变状态无关。与此相反，在表达野生型HIF-1α和HIF-2α蛋白的细胞中，HIF-1α在VEGF分泌中起主导作用。HIF-1α的转录沉默或mRNA表达被截短是肾癌细胞中的普遍现象。因此，HIF-1α可能是RCC治疗的重要靶分子，但HIF-2α应靶向于HIF-1α缺陷的肾癌细胞。

Recent efforts have been aimed at targeting the hypoxia inducible factor (HIF)-mediated hypoxia induced gene pathway for renal cell carcinomas (RCC) therapy. Among the various genes induced by HIF, vascular endothelial growth factor (VEGF) is one of the critical mediators in angiogenesis, tumor growth and metastasis. To date, however, limited information is available on the functional differences regarding VEGF transcription between the HIF subunits, namely HIF-1α and HIF-2α. VHL gene was inactivated in 4 of 9 cell lines, due to frame shift mutation or hypermethylation. All four cell lines with VHL gene activation had either a truncated or defective HIF-1α expression. Transcriptional silencing, accompanying aberrant CpG island promotor region methylation or truncated mRNA expression was observed in 5 of 9 cell lines which resulted in the absence of wild type HIF-1α protein expression. The reduced potein expression was due to a low level of mRNA expression. Therefore, as a whole, protein expression was correlated with mRNA expression. In the cell lines devoid of HIF-1α expression, VEGF expression was maintained by HIF-2α expression. Indeed, 769P cell lacking both HIF-1α and HIF-2α had low VEGF expression. In these HIF-1α defective cell lines, the knockdown of the HIF-2α gene demonstrated that HIF-2α regulated the VEGF production, irrespective of the VHL gene mutation status. In contrast, HIF-1α played a predominant role in VEGF secretion in the cells expressing both wild type HIF-1α and HIF-2α proteins. The transcriptional silencing or truncated mRNA expression of HIF-1α was a common phenomenon in human RCC cell lines. HIF-1α may therefore represent an important target molecule for RCC therapy, however, HIF-2α should be targeted in HIF-1α defective renal cancer cells.