Overexpression of PIMREG promotes breast cancer aggressiveness via constitutive activation of NF-κB signaling
Overexpression of PIMREG promotes breast cancer aggressiveness via constitutive activation of NF-κB signaling
复制标题
PIMREG 过度表达通过 NF-κ B 信号传导的组成型激活促进乳腺癌侵袭性
DOI：
10.1016/j.ebiom.2019.04.001
复制
发表时间：
2019-05-01
期刊：
影响因子：
11.1
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
Jiang, Lili;Ren, Liangliang;Li, Jun
背景：核因子κ B （nf - κ B）信号的激活在癌症的发生和发展中起着重要作用。然而，NF-kappa B通路在癌症中组成性激活的潜在机制仍不清楚。本研究旨在探讨PICALM相互作用的有丝分裂调节因子（PIMREG）在维持乳腺癌nf - κ B激活中的作用。方法：通过免疫沉淀、EMSA和荧光素酶报告基因检测来确定pimreg介导的NF-kappa B构成激活的潜在机制。采用定量PCR、western blotting和免疫组化检测PIMREG的表达。采用MTT法、软琼脂克隆法、伤口愈合法、基质穿透法和体内异种移植肿瘤模型检测PIMREG对乳腺癌细胞侵袭性的影响。研究发现：PIMREG与NF-kappa B的REL同源结构域（RHD）与I kappa B α竞争性相互作用，并通过破坏NF-kappa B/I kappa B α负反馈回路促进NF-kappa B的核积累和转录活性，从而维持NF-kappa B的激活。PIMREG过表达可显著增强NF-kappa B的相互作用，促进乳腺癌侵袭性。PIMREG在乳腺癌中表达明显上调，且与乳腺癌患者临床分期、肿瘤-淋巴结-转移分型及较差生存率呈正相关。解释：PIMREG通过破坏NF-kappa B/I kappa B α负反馈回路促进乳腺癌的侵袭性，这表明PIMREG可能是转移性乳腺癌诊断和治疗的一个有价值的预后因素和潜在靶点。(C) 2019作者。Elsevier B.V.出版
Background: It is well-established that activation of nuclear factor-kappa B (NF-kappa B) signaling plays important roles in cancer development and progression. However, the underlying mechanism by which the NF-kappa B pathway is constitutively activated in cancer remains largely unclear. The present study aimed to investigate the effect of PICALM interacting mitotic regulator (PIMREG) on sustaining NF-kappa B activation in breast cancer.Methods: The underlying mechanisms in which PIMREG-mediated NF-kappa B constitutive activation were determined via immunoprecipitation, EMSA and luciferase reporter assays. The expression of PIMREG was examined by quantitative PCR and western blotting analyses and immunohistochemical assay. The effect of PIMREG on aggressiveness of breast cancer cell was measured using MTT, soft agar clonogenic assay, wound healing and transwell matrix penetration assays in vitro and a Xenografted tumor model in vivo.Findings: PIMREG competitively interacted with the REL homology domain (RHD) of NF-kappa B with I kappa B alpha, and sustained NF-kappa B activation by promotion of nuclear accumulation and transcriptional activity of NF-kappa B via disrupting the NF-kappa B/I kappa B alpha negative feedback loop. PIMREG overexpression significantly enhanced NF-kappa B transactivity and promoted the breast cancer aggressiveness. The expression of PIMREG was markedly upregulated in breast cancer and positively correlated with clinical characteristics of patients with breast cancer, including the clinical stage, tumor-node-metastasis classification and poorer survival.Interpretation: PIMREG promotes breast cancer aggressiveness via disrupting the NF-kappa B/I kappa B alpha negative feedback loop, which suggests that PIMREG might be a valuable prognostic factor and potential target for diagnosis and therapy of metastatic breast cancer. (C) 2019 The Authors. Published by Elsevier B.V.