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Prediction of in vitro response to interferon-alpha and acquisition of its susceptibility by gene and peptide transduction system

通过基因和肽转导系统预测干扰素-α的体外反应并获取其敏感性

基本信息

批准号：
18591739
负责人：
SHIMAZUI Toru
金额：
$ 2.53万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

It is important to investigate the interferon-alpha (IFN-a) sensitivity-related gene and regulation of susceptibility to IFN-α in renal cell carcinoma (RCC). First, we have identified seven candidate genes, which are associated with IFN-a-response and then established prediction formula using four genes, I.e. ADFP, MITF, MTUS1, and TNNT1, in RCC cell lines. Validation of this prediction model was performed in other RCC cell lines, including primary culture cells from patients with RCC. We next focused MITF gene, which individually correlated with IFN-α-sensitivity, to analyze relationship between its expression and IFN-α-response status by gene transfection. MITF transfectant demonstrated susceptibility in IFN-α-resistant line as compared with wild type or mock transfectant. Because MITF is one off transcription factor, which can bind to p16 and HIF-1α, it is suggested that MITF may be associated with development and progression of RCC acceleration of cell cycle. Thus, we evaluated expression of p16 and anti-tumor effect of biological active p16 peptide (p16-MIS) by peptide transduction system with Wr-T transporter peptide. All RCC cell lines used are absent for p16 protein, even in the IFN-α-resistant RCC MITF-transfectant. P16-MIS successfully transferred into cellular cytoplasm and nucleus of RCC cells by concentration dependent manner. Interestingly, IFN-α-susceptibility was acquired at 2.5 to 100 times intensity in IFN-α-resistant RCC cell line. These results suggested that IFN-α-response related gene, MITF and its related cell cycle regulator, p16 could be molecular targets in therapeutic strategy of RCC.

研究干扰素-α（IFN-α）敏感性相关基因及其在肾细胞癌（RCC）中的作用具有重要意义。首先，我们已经确定了七个候选基因，这是与IFN-α-反应，然后建立预测公式，使用四个基因，即ADFP，MITF，MTUS 1，和TNNT 1，在RCC细胞系。该预测模型的验证在其他RCC细胞系中进行，包括来自RCC患者的原代培养细胞。接下来我们聚焦与IFN-α敏感性相关的MITF基因，通过基因转染分析其表达与IFN-α应答状态的关系。MITF转染子在IFN-α抗性株中表现出敏感性，与野生型或模拟转染子相比。由于MITF是一种与p16和HIF-1α结合的非特异性转录因子，提示MITF可能与肾细胞癌的发生发展有关。因此，我们利用含p16-T转运肽的肽转导系统，研究了p16的表达和生物活性p16肽（p16-MIS）的抗肿瘤作用。所有使用的RCC细胞系都不存在p16蛋白，即使在IFN-α抗性RCC MITF转染子中也是如此。P16-MIS以浓度依赖的方式成功地转移到RCC细胞的细胞质和细胞核中。有趣的是，在IFN-α抗性RCC细胞系中，IFN-α敏感性在2.5至100倍强度下获得。提示IFN-α反应相关基因MITF及其相关的细胞周期调控因子p16可作为肾癌治疗的分子靶点。