通过肿瘤基因组筛选鉴定针对肝癌中扩增 FGF19 的治疗策略。
Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening.
机构信息
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
出版信息
Cancer Cell. 2011 Mar 8;19(3):347-58. doi: 10.1016/j.ccr.2011.01.040.
Abstract
We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.
摘要
我们使用小鼠肝母细胞瘤模型筛选了 124 个在人类肝细胞癌（HCC）中扩增的基因，并鉴定出了 18 个促进肿瘤的基因，包括 CCND1 及其在 11q13.3 上的邻居 FGF19。虽然人们普遍认为 CCND1 是这个常见扩增子（HCC 中的频率为 15%）的主要驱动致癌基因，但正向转化实验和人类 HCC 细胞中的 RNAi 介导抑制实验都表明 FGF19 是 HCC 中同样重要的驱动基因。此外，携带 11q13.3 扩增子的 HCC 细胞的克隆生长和致瘤性可通过 RNAi 介导的 CCND1 或 FGF19 敲低以及抗 FGF19 抗体选择性抑制。这些结果表明，11q13.3 扩增可能是对抗 FGF19 治疗最可能有反应的患者的有效生物标志物。
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