Overexpression of PIMREG promotes breast cancer aggressiveness via constitutive activation of NF-κB signaling.

Abstract

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.

• Authors: Lili Jiang, Liangliang Ren, Xiaolan Zhang, Han Chen, Xuhong Chen, Chun Lin, Lan Wang, Ning Hou, Jinyuan Pan, Zhongqiu Zhou, Hongbiao Huang, Danping Huang, Jianan Yang, Yingying Liang, Jun Li
• Journal: EBioMedicine (EBioMedicine) Vol. 43 Pg. 188-200 (May 2019) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30979686 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Intracellular Signaling Peptides and Proteins
• NF-kappa B
• Nuclear Proteins
• PIMREG protein, human

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, mortality, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Epithelial Cells (metabolism)
• Female
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Humans
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice
• Models, Biological
• NF-kappa B (metabolism)
• Nuclear Proteins (genetics, metabolism)
• Prognosis
• Signal Transduction
• Xenograft Model Antitumor Assays