Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1.
Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1.
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DOI：
10.1371/journal.pgen.1002855
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Chen CZ
中科院分区：
文献类型：
--
作者：
Fragoso R;Mao T;Wang S;Schaffert S;Gong X;Yue S;Luong R;Min H;Yashiro-Ohtani Y;Davis M;Pear W;Chen CZ
癌基因是肿瘤发生、发展和维持所必需的，是癌症治疗的有价值的靶点。然而，它仍然是一个挑战，有效地抑制癌基因的活性，通过靶向其下游途径，而不造成显着的毒性正常组织。在这里，我们表明，删除mir-181 a-1/B-1表达抑制Notch 1癌基因诱导的T细胞急性淋巴细胞白血病（T-ALL）的发展。mir-181 a-1/B-1部分通过抑制NOTCH和前T细胞受体（TCR）信号传导途径下游的多个负反馈调节因子来控制肿瘤发生中Notch活性的强度和阈值。重要的是，尽管Notch癌基因利用正常胸腺祖细胞遗传程序进行肿瘤转化，但对正常胸腺细胞和肿瘤发展中的mir-181 a-1/B-1功能的比较分析表明，mir-181 a-1/B-1可以特异性靶向抑制肿瘤发展，对正常发展的毒性很小。最后，我们证明了mir-181 a-1/B-1，而不是mir-181 a-2 B-2和mir-181-c/d，控制正常胸腺T细胞和白血病细胞的发育。总之，这些结果表明，肿瘤发展中的NOTCH癌基因活性可以通过靶向由mir-181 a-1/B-1控制的分子网络来选择性抑制。癌基因引发肿瘤发生、发展和维持所需的驱动信号，并且是癌症治疗的有价值的靶标。然而，癌基因通常在正常细胞生理学中具有基本功能，并且产生难以用小分子药物抑制而不对正常组织造成显著毒性的细胞内蛋白。因此，癌症治疗中的挑战之一是确定可以靶向特异性抑制肿瘤细胞中的致癌信号而不损害正常组织的下游网络。在这项研究中，我们证明了微小RNA（miRNA）基因mir-181 a-1/B-1的缺失，特异性抑制肿瘤发生中Notch癌基因的活性，而不会导致正常发育的显著缺陷。尽管早期研究已经优雅地表明了NOTCH和前TCR信号在NOTCH诱导的肿瘤发生中的重要作用，但由于其治疗效果较弱且毒性严重，NOTCH和前TCR信号都无法有效靶向用于现有药物治疗T-ALL。我们的研究结果表明，解剖miRNAs的下游靶标可以揭示可以靶向控制癌基因引起的肿瘤转化的分子网络。更重要的是，我们的研究结果表明，对正常细胞和肿瘤细胞所利用的途径的比较研究可能会揭示新的见解，如何致瘤途径可能被选择性地抑制，对正常组织的损害有限。
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. Oncogenes elicit driving signals required for tumor initiation, development, and maintenance and are valuable targets for cancer therapy. However, oncogenes often have essential functions in normal cellular physiology and produce intracellular proteins that are difficult to inhibit with small molecule drugs without causing significant toxicity to normal tissues. Thus, one of the challenges in cancer therapy is to identify downstream networks that can be targeted to specifically dampen the oncogenic signals in tumor cells without harming normal tissues. In this study we demonstrate that deletion of a microRNA (miRNA) gene, mir-181a-1/b-1, specifically inhibits the activity of the Notch oncogene in tumorigenesis without causing significant defects in normal development. Although earlier studies have elegantly shown the essential role of NOTCH and pre-TCR signals in NOTCH-induced tumorigenesis, neither NOTCH nor pre-TCR signals can be targeted effectively for treatment of T-ALL with available drugs due to their weak therapeutic effects and severe toxicities. Our findings illustrate that dissecting the downstream targets of miRNAs can reveal the molecular networks that can be targeted to control tumor transformation caused by oncogenes. More importantly, our results illustrate that comparative studies on the pathways utilized by normal cells and tumor cells may reveal novel insights into how tumorigenic pathways may be selectively inhibited with limited damage to normal tissues.
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影响因子：
4.4
作者：
Ciofani, M;Schmitt, TM;Zúñiga-Pflücker, JC
通讯作者：
Zúñiga-Pflücker, JC
影响因子：
30.5
作者：
Schmitt, TM;de Pooter, RF;Zúñiga-Pflücker, JC
通讯作者：
Zúñiga-Pflücker, JC
CERNA假设：隐藏RNA语言的Rosetta石头？
影响因子：
64.5
作者：
Salmena L;Poliseno L;Tay Y;Kats L;Pandolfi PP
通讯作者：
Pandolfi PP
DOI：
10.1073/pnas.0602266103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Costinean, S;Zanesi, N;Croce, CM
通讯作者：
Croce, CM
影响因子：
20.3
作者：
Campese, Antonio F.;Garbe, Annette I.;von Boehmer, Harald
通讯作者：
von Boehmer, Harald