Combined Functional Genome Survey of Therapeutic Targets for Hepatocellular Carcinoma
Combined Functional Genome Survey of Therapeutic Targets for Hepatocellular Carcinoma
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DOI：
10.1158/1078-0432.ccr-09-2214
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发表时间：
2010-05-01
影响因子：
11.5
通讯作者：
Yamada, Tesshi
中科院分区：
文献类型：
--
作者：
Satow, Reiko;Shitashige, Miki;Yamada, Tesshi
目的：晚期肝细胞癌（HCC）患者的预后一直不令人满意。HCC患者患有慢性肝炎或肝硬化，他们的储备肝功能通常有限。实验设计：为了开发特异性作用于HCC但仅最低限度地干扰残余肝功能的新治疗剂，我们搜索了在20例HCC中上调的基因[即，发现集1（n = 10）和2（n = 10）]与相应的非肿瘤性肝脏和代表正常器官的面板进行比较，使用能够检测人类基因组中所有外显子的高密度微阵列。对HCC中表达显著增加的11个转录物进行基于siRNA的HCC细胞增殖所需基因的二次筛选以及定量逆转录-PCR分析[验证集1（n = 20）]。和2（n = 44）]和免疫组化（n = 19）。我们最终提取了AKR 1B 10、HCAP-G、RRM 2和TPX 2四个基因作为HCC的候选治疗靶点。siRNA介导的这些候选基因的敲低抑制肝癌细胞的增殖和肝癌异种移植到免疫缺陷mice.Conclusions的生长：我们确定的四个基因是高表达的肝癌，肝癌细胞是高度依赖于这些基因的增殖。虽然许多重要的基因肯定被忽略了，但被选中的基因在生物学上是相关的。这里描述的全基因组表达和功能筛选的组合是一种快速和全面的方法，可以应用于任何类型的人类恶性肿瘤的治疗靶点的鉴定。临床癌症研究; 16（9）; 2518-28。(C)2010年AACR。
Purpose: The outcome of patients with advanced hepatocellular carcinoma (HCC) has remained unsatisfactory. Patients with HCC suffer from chronic hepatitis or liver cirrhosis, and their reserve liver function is often limited.Experimental Design: To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we searched for genes that were upregulated in 20 cases of HCC [namely, discovery sets 1 (n = 10) and 2 (n = 10)] in comparison with corresponding nontumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome.Results: Eleven transcripts whose expression was significantly increased in HCC were subjected to siRNA-based secondary screening of genes required for HCC cell proliferation as well as quantitative reverse transcription-PCR analysis [validation sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted four genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice.Conclusions: The four genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Although many important genes must have been overlooked, the selected genes were biologically relevant. The combination of genome-wide expression and functional screening described here is a rapid and comprehensive approach that could be applied in the identification of therapeutic targets in any type of human malignancy. Clin Cancer Res; 16(9); 2518-28. (C) 2010 AACR.