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首页> 外文期刊>Oncogene >Nuclear KIT induces a NFKBIB-RELA-KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors
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Nuclear KIT induces a NFKBIB-RELA-KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors

机译:核试剂盒在伊马替尼抗性胃肠道基质肿瘤中诱导NFKBIB-RELA-kit自身调节环

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摘要

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.
机译:胃肠道基质肿瘤(GIST)经常由自动活化的突变试剂盒驱动,并对试剂盒酪氨酸激酶抑制剂具有耐用的反应。然而,获得的抗性是接受前线伊马替尼治疗的GIST患者的临床问题。我们以前的研究表明,在GIST细胞中与DAPI染色的细胞核在不知道核试剂盒在GIST肿瘤发生中的作用的情况下,套件的分致化。在本文中,我们首先将核试剂盒与染色质免疫沉淀(芯片)测序和切屑测定的核试剂抑制剂β(NFKBIB)的启动子的结合鉴定为伴随着基因细胞中的增强的NFKBIB蛋白表达。临床上,与中间或低/极低/非常低/非常低风险的GISTS相比,高NCCN风险GIST具有显着更高的核磷酸盐试剂盒和NFKBIB的表达水平。相反,SiRNA对NFKBIB的下调导致Rela核转位,可与试剂盒启动子区域结合,随后降低试剂盒转录/表达和GIST细胞的活力。通过Rela过表达或NFKB / rela诱导剂,丙戊酸,治疗进一步证实这些发现,以导致胰岛素抗性剂细胞的套件表达和相对细胞活力。将丙戊酸与伊马替尼结合在体外对伊替尼抗性GYS48和GYS430细胞的显着更好的增长抑制作用,并且在GYS430动物异种移植模型中。这些结果一起展示了在GIST肿瘤发生中的核试剂盒驱动的NFKBIB-RERA-KIT自身疗法的存在性,这是开发联合治疗的潜在靶标,以克服表达套件的胰岛素抗性。

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