PIMREG 的过表达通过 NF-κB 信号的组成性激活促进乳腺癌的侵袭性。
Overexpression of PIMREG promotes breast cancer aggressiveness via constitutive activation of NF-κB signaling.
机构信息
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
出版信息
EBioMedicine. 2019 May;43:188-200. doi: 10.1016/j.ebiom.2019.04.001. Epub 2019 Apr 9.
BACKGROUND
It is well-established that activation of nuclear factor-kappa B (NF-κB) signaling plays important roles in cancer development and progression. However, the underlying mechanism by which the NF-κB 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-κB activation in breast cancer.
METHODS
The underlying mechanisms in which PIMREG-mediated NF-κB 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-κB with IκBα, and sustained NF-κB activation by promotion of nuclear accumulation and transcriptional activity of NF-κB via disrupting the NF-κB/IκBα negative feedback loop. PIMREG overexpression significantly enhanced NF-κB 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-κB/IκBα negative feedback loop, which suggests that PIMREG might be a valuable prognostic factor and potential target for diagnosis and therapy of metastatic breast cancer. FUND: The science foundation of China, Guangdong Province, Guangzhou Education System, and the Science and Technology Program of Guangzhou.
背景
核因子-κB（NF-κB）信号的激活在癌症的发生和发展中起着重要作用，这一点已得到充分证实。然而，NF-κB 通路在癌症中持续激活的潜在机制在很大程度上仍不清楚。本研究旨在探讨 PICALM 相互作用的有丝分裂调节剂（PIMREG）在维持乳腺癌中 NF-κB 激活中的作用。
方法
通过免疫沉淀、电泳迁移率变动分析和荧光素酶报告基因分析确定了 PIMREG 介导的 NF-κB 组成性激活的潜在机制。通过定量 PCR 和 Western blot 分析及免疫组织化学检测分析了 PIMREG 的表达。通过体外 MTT、软琼脂克隆形成试验、划痕愈合和 Transwell 基质渗透试验以及体内异种移植肿瘤模型，检测了 PIMREG 对乳腺癌细胞侵袭性的影响。
发现
PIMREG 与 NF-κB 的 REL 同源结构域（RHD）竞争相互作用与 IκBα，并通过破坏 NF-κB/IκBα 负反馈环，促进核积累和 NF-κB 的转录活性，从而持续激活 NF-κB。PIMREG 过表达显著增强了 NF-κB 的转录活性，并促进了乳腺癌的侵袭性。PIMREG 在乳腺癌中的表达明显上调，并与乳腺癌患者的临床特征呈正相关，包括临床分期、肿瘤-淋巴结-转移分类和较差的生存率。
结论
PIMREG 通过破坏 NF-κB/IκBα 负反馈环促进乳腺癌的侵袭性，这表明 PIMREG 可能是一个有价值的预后因素和转移性乳腺癌诊断和治疗的潜在靶点。
资助
中国科学基金会、广东省、广州市教育系统和广州市科技计划。
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