Modulating the Strength and Threshold of NOTCH Oncogenic Signals by <em>mir-181a-1/b-1</em>

Oncogenes, which are essential for tumor initiation, development, and maintenance, are valuable targets for cancer therapy. However, it remains a challenge to effectively inhibit oncogene activity by targeting their downstream pathways without causing significant toxicity to normal tissues. Here we show that deletion of mir-181a-1/b-1 expression inhibits the development of Notch1 oncogene-induced T cell acute lymphoblastic leukemia (T-ALL). mir-181a-1/b-1 controls the strength and threshold of Notch activity in tumorigenesis in part by dampening multiple negative feedback regulators downstream of NOTCH and pre-T cell receptor (TCR) signaling pathways. Importantly, although Notch oncogenes utilize normal thymic progenitor cell genetic programs for tumor transformation, comparative analyses of mir-181a-1/b-1 function in normal thymocyte and tumor development demonstrate that mir-181a-1/b-1 can be specifically targeted to inhibit tumor development with little toxicity to normal development. Finally, we demonstrate that mir-181a-1/b-1, but not mir-181a-2b-2 and mir-181-c/d, controls the development of normal thymic T cells and leukemia cells. Together, these results illustrate that NOTCH oncogene activity in tumor development can be selectively inhibited by targeting the molecular networks controlled by mir-181a-1/b-1.致癌基因对于肿瘤的发生、发展与维持至关重要，是癌症治疗的重要靶点。然而，通过靶向致癌基因的下游通路以有效抑制其活性，同时不对正常组织造成显著毒性，仍是一项挑战。本研究证实，敲除mir-181a-1/b-1的表达可抑制Notch1致癌基因诱导的T细胞急性淋巴细胞白血病（T-ALL）的发生发展。mir-181a-1/b-1可在肿瘤发生过程中调控Notch活性的强度与阈值，其部分机制是通过抑制NOTCH下游及前T细胞受体（TCR）信号通路中的多个负反馈调控因子。值得注意的是，尽管Notch致癌基因利用正常胸腺祖细胞的遗传程序完成肿瘤转化，但针对mir-181a-1/b-1在正常胸腺细胞与肿瘤发育中的功能开展的比较分析显示，mir-181a-1/b-1可被特异性靶向以抑制肿瘤发展，且对正常发育的毒性极小。最后，本研究证实，仅mir-181a-1/b-1（而非mir-181a-2/b-2与mir-181c/d）可调控正常胸腺T细胞与白血病细胞的发育。综上，上述结果表明，可通过靶向mir-181a-1/b-1所调控的分子网络，选择性抑制肿瘤发展过程中NOTCH致癌基因的活性。