Bric Anka, Miething Cornelius, Bialucha Carl Uli, Scuoppo Claudio, Zender Lars, Krasnitz Alexander, Xuan Zhenyu, Zuber Johannes, Wigler Michael, Hicks James, McCombie Richard W, Hemann Michael T, Hannon Gregory J, Powers Scott, Lowe Scott W
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cancer Cell. 2009 Oct 6;16(4):324-35. doi: 10.1016/j.ccr.2009.08.015.
Short hairpin RNAs (shRNAs) capable of stably suppressing gene function by RNA interference (RNAi) can mimic tumor-suppressor-gene loss in mice. By selecting for shRNAs capable of accelerating lymphomagenesis in a well-characterized mouse lymphoma model, we identified over ten candidate tumor suppressors, including Sfrp1, Numb, Mek1, and Angiopoietin 2. Several components of the DNA damage response machinery were also identified, including Rad17, which acts as a haploinsufficient tumor suppressor that responds to oncogenic stress and whose loss is associated with poor prognosis in human patients. Our results emphasize the utility of in vivo RNAi screens, identify and validate a diverse set of tumor suppressors, and have therapeutic implications.
能够通过RNA干扰（RNAi）稳定抑制基因功能的短发夹RNA（shRNA）可模拟小鼠体内肿瘤抑制基因的缺失。通过在一个特征明确的小鼠淋巴瘤模型中筛选能够加速淋巴瘤发生的shRNA，我们鉴定出了十多种候选肿瘤抑制因子，包括分泌型卷曲相关蛋白1（Sfrp1）、麻木蛋白（Numb）、丝裂原活化蛋白激酶激酶1（Mek1）和血管生成素2。还鉴定出了DNA损伤反应机制的几个组成部分，包括Rad17，它作为一种单倍体不足的肿瘤抑制因子，对致癌应激作出反应，其缺失与人类患者的不良预后相关。我们的结果强调了体内RNAi筛选的实用性，鉴定并验证了多种肿瘤抑制因子，具有治疗意义。
