Functional genome survey of RCC.
Functional genome survey of RCC.
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RCC 功能基因组调查。
DOI：
10.1093/jjco/hyr060
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Ito H,Honda K,Satow R,Arai E,Shitashige M. et al.
中科院分区：
文献类型：
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作者：
Kashima L;Idogawa M;Mita H;Shitashige M. et al.;Ito H,Honda K,Satow R,Arai E,Shitashige M. et al.
目的新出现的分子靶向治疗药物已被应用于晚期肾癌的治疗，但其疗效仍然有限。本研究的目的是对肾癌的潜在治疗靶分子进行分类。方法我们首先使用高密度外显子阵列选择了10例患者肾透明细胞癌中相对于周围正常肾组织上调表达的基因(研究队列)，该外显子阵列检测了所有在人类基因组中预测的潜在转录本。通过实时逆转录聚合酶链式反应和小干扰核糖核酸在6个肾透明细胞癌细胞系中的功能筛选，我们在另一组10例患者(验证队列)中对所选基因进行了独立验证。结果我们鉴定了164个在透明细胞肾癌中表达显著升高的基因(P<；0.0001[学生t检验]和至少3倍的转录信号变化)。我们最终从至少两个肾透明细胞癌细胞系中提取了维持细胞增殖所需的33个基因。这33个基因包括13个已知与肾癌发生发展相关的基因，包括CAIX和Flt-1，证实了当前策略的稳健性。结论通过全基因组表达和功能分析相结合的方法，我们筛选出一组具有药物开发潜力的基因。该方法快速、全面，可用于寻找除肾透明细胞癌以外的其他肿瘤的诊断标志物和治疗靶点。
ObjectiveEmerging molecular targeting therapeutics have been incorporated into the management of advanced renal cell carcinoma; however, their efficacy remains limited. The aim of this study was to catalog potential therapeutic target molecules for renal cell carcinoma.MethodsWe first selected genes up-regulated in clear cell renal cell carcinoma relative to surrounding normal kidney tissues in 10 patients (Study Cohort) using high-density exon arrays that detect all potential transcripts predicted in the human genome. The selected genes were subjected to independent validation in another set of 10 patients (Validation Cohort) using real-time reverse transcriptase polymerase chain reaction and functional screening using small interfering RNA in six clear cell renal cell carcinoma cell lines.ResultsWe identified 164 genes whose expression was significantly elevated in clear cell renal cell carcinoma (P< 0.0001 [Student'st-test] and at least a 3-fold change in transcription signal). We finally extracted 33 genes required for maintaining cell proliferation in at least two clear cell renal cell carcinoma cell lines. The 33 genes included 13 genes known to be associated with the development/progression of renal cell carcinoma, includingCAIXandFLT-1, confirming the robustness of the current strategy.ConclusionsThrough a combination of genome-wide expression and functional assays, we identified a set of genes with high potential as targets for drug development. This method is rapid and comprehensive and could be applied to the discovery of diagnostic biomarkers and therapeutic targets for cancers other than clear cell renal cell carcinoma.