Gene expression profiling in association with interferon-alpha-sensitivity for the personalized treatment of renal cell carcinoma

肾细胞癌个体化治疗中与干扰素-α敏感性相关的基因表达谱分析

• 批准号: 15591669
• 负责人: SHIMAZUI Toru
• 金额: $ 2.24万
• 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: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591669/
• 关键词: Microarray; Interferon-alpha; Kidney neoplasms; Gene expression profile; インターフェロン; 分子標的; 薬剤感受性; 網羅的解析; 遺伝子発現

Background. We analyzed the correlation between interferon-α (IFNα) response and gene expression profiles to predict IFNα sensitivity and identified key molecules regulating the IFNα response in renal cell carcinoma (RCC).Methods. To evaluate patients with RCC according to IFNα-response, gene expression profiling was done using 3,840 clones microarray, and then IFNα-responder related genes were selected by clustering analysis. Basically, IFNα-response of RCC cell lines was evaluated by MTT assay with 300 to 10,000 IU/ml of IFNα treatment. Microarray, followed by supervised hierarchical clustering analysis, was applied to selected genes according to IFNα sensitivity. In order to find alteration of expression profiles induced by IFNα, sequential microarray analyses were performed at 3,6, and 12 hrs after IFNα treatment of RCC cell lines and mRNA expression level was confirmed using quantitative RT-PCR. A model for prediction of IFNα response was created according to the statistical correlation between gene expression profiles and IFNα-sensitivity.Results. According to microarray analysis in 14 patients with RCC,IFNα-responder might be identified by the selected gene sets. Microarray followed clustering analysis between IFNα-sensitive and IFNα-resistant line, seven genes, ADFP,MITF,MTUS1,PME-1,MLLT3,MLF1, and TNNT1, were eventually selected as candidates for IFNα-sensitivity-related genes in RCC cell lines. We further developed a model to predict tumor-inhibition with four molecules, i.e., ADFP,MITF,MTUS1, and TNNT1, using multiple linear regression analysis (coefficient=0.948,p=0.0291) and validated the model using primary cultured RCC cells.Conclusions. The expression levels of the combined selected genes can provide predictive information on the IFNα response in RCC. Furthermore, the IFNα-response to RCC might be modulated by regulation of the expression level of these molecules.

背景我们分析了干扰素-α（IFNα）反应与基因表达谱之间的相关性，以预测IFNα敏感性，并确定了调节肾癌（RCC）IFNα反应的关键分子。为了根据IFNα应答评估RCC患者，使用3，840个克隆的基因表达谱芯片进行基因表达谱分析，然后通过聚类分析选择IFNα应答相关基因。基本上，RCC细胞系的IFNα应答通过MTT测定用300至10，000 IU/ml的IFNα处理来评价。微阵列，然后监督分层聚类分析，应用于选定的基因，根据IFNα的敏感性。为了观察IFNα对肾癌细胞基因表达谱的影响，采用基因芯片技术，在IFNα处理肾癌细胞3、6、12 h后，用定量RT-PCR检测mRNA表达水平。根据基因表达谱与IFNα敏感性之间的统计学相关性，建立了IFNα应答预测模型。根据14例肾细胞癌患者的基因芯片分析，选择的基因集可能是确定IFNα应答者的依据。通过基因芯片对IFNα敏感株和IFNα耐药株进行聚类分析，最终筛选出ADFP、MITF、MTUS 1、PME-1、MLLT 3、MLF 1和TNNT 1 7个基因作为肾癌细胞IFNα敏感相关基因的候选基因。我们进一步开发了一个模型来预测四种分子的肿瘤抑制作用，即，ADFP、MITF、MTUS 1和TNNT 1的表达水平进行多元线性回归分析（相关系数= 0.948，p =0.0291），并以原代培养的肾细胞癌细胞为模型进行验证。联合选择的基因的表达水平可以提供关于RCC中IFNα应答的预测信息。此外，IFNα对RCC的反应可能通过调节这些分子的表达水平来调节。

项目成果

Gene Expression Profiling Identifies Platelet-Derived Growth Factor as a Diagnostic Molecular Marker for Papillary Thyroid Carcinoma

• DOI: 10.1158/1078-0432.ccr-0807-03
• 发表时间: 2004-03
• 期刊: Clinical Cancer Research
• 影响因子: 11.5
• 作者: Yukiko Yano;N. Uematsu;T. Yashiro;H. Hara;E. Ueno;M. Miwa;G. Tsujimoto;Y. Aiyoshi;K. Uchida

鳥居 徹, 他: "進行腎癌に対するインターフェロンα治療テーラーメイド化のための基礎的検討"癌の臨床. 50. 7-13 (2004)

Toru Torii 等人：“针对晚期肾癌定制干扰素 α 治疗的基础研究”癌症临床研究 50. 7-13 (2004)。

進行腎癌に対するインターフェロンα治療テーラーメード化のための基礎的検討

干扰素α个体化治疗晚期肾癌的基础研究

• 发表时间: 2004
• 期刊: 癌の臨床 50
• 作者: 島居 徹;他
• 通讯作者: 他

Differential profiling analysis of proteins involved in anti-proliferative effect of interferon-alpha on renal cell carcinoma cell lines by protein biochip technology

利用蛋白质生物芯片技术对干扰素-α对肾细胞癌细胞系的抗增殖作用相关蛋白质进行差异分析

• 发表时间: 2006
• 期刊: Int J Oncol 28
• 作者: Nakamura K;Shimazui;T;et al.
• 通讯作者: et al.

Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines.

干扰素-α 在肝细胞癌细胞系中快速抑制 MAPK 信号传导并通过 JAK/STAT 信号传导发挥抗增殖作用。

• 发表时间: 2005
• 期刊: Biochim. Biophys. Acta. 1745
• 作者: Honda A et al.;Honda A et al.;Honda A et al.;Honda A et al.;Honda A et al.;Honda A et al.;Matsuzaki Y et al.;Hirayama T et al.;Matsuzaki Y et al.;Matsuzaki Y et al.;Hirayama T et al.;Zhang Y et al.;Jiang Y et al.;Inamura K et al.
• 通讯作者: Inamura K et al.