Analyses of altered VHL protein function in the clear cell renal carcinoma(CRCC) and its utilization for CRCC patients.

透明细胞肾癌 (CRCC) 中 VHL 蛋白功能改变的分析及其在 CRCC 患者中的应用。

• 批准号: 23592334
• 负责人: SHUIN TARO
• 金额: $ 3.41万
• 依托单位: Kochi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23592334/
• 关键词: VHL遺伝子変異; HIF1α; HIF2α; ES細胞; VHL遺伝子; 腎癌; 腎細胞癌; von Hippel-Lindau病; HIF1a; HIF2a; VHLノックアウトマウス

Clear cell renal cell carcinoma (CCRCC) is one of the most common pathological type in kidney cancer. VHL gene mutation results in the accumulation of HIF1a and HIF2a protein. Accumulation of HIF protein results in the increased expression of VEGF proteins. Currently many molecular targeting drugs for VEGF receptor are one of the most popular treatments for metastatic kidney cancers. However, it should be noted that some of mutant VHL protein has a residual normal function or altered other function.To elucidate the residual or altered function in the mutant protein we introduced mutant VHL gene detected in CCRCC to VHL double knockout mouse embryonal fibroblasts(MEFs), and we could develop MEF1 and MEF2. Only one mutant VHL protein resulted in the decreased function in HIF1a. Other mutant VHL protein could not result in the similar changes. To understand CCRCC and its treatment option, we would like to analyze altered function in mutant VHL proteins further.

肾透明细胞癌是肾癌中最常见的病理类型之一。VHL基因突变导致HIF 1a和HIF 2a蛋白的积累。HIF蛋白的积累导致VEGF蛋白的表达增加。目前针对VEGF受体的分子靶向药物是治疗转移性肾癌的最常用药物之一。然而，应该注意的是，一些突变的VHL蛋白具有残留的正常功能或改变的其他功能，为了阐明突变蛋白中的残留或改变的功能，我们将在CCRCC中检测到的突变的VHL基因导入VHL双敲除小鼠胚胎成纤维细胞（MEF），我们可以获得MEF 1和MEF 2。只有一个突变的VHL蛋白导致HIF 1a的功能下降。 其他突变VHL蛋白则不能引起类似的变化。为了了解CCRCC及其治疗选择，我们希望进一步分析突变VHL蛋白的功能改变。