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Hypoxia responsiveness in renal cell carcinoma

肾细胞癌的缺氧反应

基本信息

批准号：
17591701
负责人：
OYA Mototsugu
金额：
$ 2.3万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591701/
关键词：
hypoxia renal cell carcinoma hypoxia inducible factor vascular endothelial growth factor VEGF HIF VHL

项目摘要

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.

近年来，人们致力于通过缺氧诱导因子（HIF）介导的缺氧诱导基因途径治疗肾细胞癌（RCC）。在HIF诱导的多种基因中，血管内皮生长因子（vascular endothelial growth factor， 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株细胞系中有4株VHL基因因移框突变或高甲基化而失活。所有四种VHL基因激活的细胞系都有截断或缺陷的HIF-1α表达。9株细胞系中有5株出现转录沉默、CpG岛启动子区甲基化异常或mRNA表达截断，导致野生型HIF-1α蛋白表达缺失。蛋白表达减少是由于mRNA表达水平较低。因此，从整体上看，蛋白表达与mRNA表达呈正相关。在缺乏HIF-1α表达的细胞系中，通过表达HIF-2α来维持VEGF的表达。事实上，缺乏HIF-1α和HIF-2α的769P细胞VEGF表达较低。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。相比之下，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转录沉默或mRNA表达截断是人RCC细胞系的普遍现象。因此，HIF-1α可能是RCC治疗的重要靶分子，然而，HIF-2α应该靶向HIF-1α缺陷的肾癌细胞。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

c-Jun activation in acquired cystic kidney disease and renal cell carcinoma

DOI：
10.1097/01.ju.0000164656.99251.77
发表时间：
2005-08-01
期刊：
JOURNAL OF UROLOGY
影响因子：
6.6
作者：
Oya, M;Mikami, S;Murai, M
通讯作者：
Murai, M

Interleukin 6 is associated with cahexia in patients with prostate cancer.

白细胞介素 6 与前列腺癌患者的失血有关。

DOI：
发表时间：
2007
期刊：
Urology 69
影响因子：
0
作者：
Kuroda;K.;Nakashima;J.;Kanao;K.;Kikuchi;E.;Miyajima;A.;Horiguchi;Y.;Nakagawa K.;Oya;M.;Ohigashi;T.;Mrai;M.
通讯作者：
M.

Repeated regression of pulmonary metastases from renal cell carcinoma after treatment using different interferon-alfa preparations.

使用不同的干扰素-α制剂治疗后肾细胞癌肺转移反复消退。