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Discovery of the Oncogenic Parp1, a Target of bcr-abl and a Potential Therapeutic, in mir-181a/PPFIA1 Signaling Pathway
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2019-02-08 , DOI: 10.1016/j.omtn.2019.01.015
Chunming Gu , Yanjun Liu , Zhao Yin , Juhua Yang , Guiping Huang , Xuejiao Zhu , Yumin Li , Jia Fei

miR-181a is downregulated in leukemia and affects its progression, drug resistance, and prognosis. However, the exact mechanism of its targets in leukemia, particularly in chronic myelogenous leukemia (CML), has not previously been established. Here, we use a multi-omics approach to demonstrate that protein tyrosine phosphatase, receptor type, f polypeptide, leukocyte common antigen (LAR) interacting protein (liprin), alpha 1 (PPFIA1) is a direct target for miR-181a in CML. Phospho-array assay shows that multiple phosphorylated proteins, particularly KIT signaling molecules, were downregulated in PPFIA1 inhibition. Additionally, PPFIA1 bound PARP1, a common molecule downstream of both PPFIA1 and BCR/ABL, to upregulate KIT protein through activation of nuclear factor kappa B (NF-κB)-P65 expression. Targeted inhibition of PPFIA1 and PARP1 downregulated c-KIT level, inhibited CML cell growth, and prolonged mouse survival. Overall, we report a critical regulatory miR-181a/PPFIA1/PARP1/NF-κB-P65/KIT axis in CML, and our preclinical study supports that targeted PPFIA1 and PARP1 may serve as a potential CML therapy.

中文翻译:


在 mir-181a/PPFIA1 信号通路中发现致癌 Parp1、bcr-abl 的靶点和潜在的治疗药物



miR-181a 在白血病中下调并影响其进展、耐药性和预后。然而,其治疗白血病,特别是慢性粒细胞白血病(CML)的确切机制此前尚未确定。在这里,我们使用多组学方法来证明蛋白酪氨酸磷酸酶、受体类型、f 多肽、白细胞共同抗原 (LAR) 相互作用蛋白 (liprin)、α 1 (PPFIA1) 是 CML 中 miR-181a 的直接靶点。磷酸化阵列分析显示,多种磷酸化蛋白,特别是 KIT 信号分子,在 PPFIA1 抑制中下调。此外,PPFIA1 结合 PARP1(PPFIA1 和 BCR/ABL 下游的常见分子),通过激活核因子 kappa B (NF-κB)-P65 表达来上调 KIT 蛋白。靶向抑制 PPFIA1 和 PARP1 可以下调 c-KIT 水平,抑制 CML 细胞生长,并延长小鼠存活时间。总体而言,我们报告了 CML 中的关键调节 miR-181a/PPFIA1/PARP1/NF-κB-P65/KIT 轴,并且我们的临床前研究支持靶向 PPFIA1 和 PARP1 可能作为潜在的 CML 治疗。
更新日期:2019-02-08
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