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

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

doi:10.1016/j.ebiom.2019.04.001

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

EBioMedicine. 2019 May:43:188-200. doi: 10.1016/j.ebiom.2019.04.001. Epub 2019 Apr 9.

Authors

Lili Jiang¹, Liangliang Ren², Xiaolan Zhang¹, Han Chen¹, Xuhong Chen¹, Chun Lin¹, Lan Wang³, Ning Hou⁴, Jinyuan Pan¹, Zhongqiu Zhou¹, Hongbiao Huang¹, Danping Huang⁵, Jianan Yang⁶, Yingying Liang⁷, Jun Li⁸

Affiliations

¹ 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.
² 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.
³ Department of Pathogen Biology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou 510006, China.
⁴ Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
⁵ Department of Ultrasonography, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
⁶ 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 Urologic Oncosurgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.
⁷ 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 Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.
⁸ 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. Electronic address: lijun37@mail.sysu.edu.cn.

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.

Keywords: Breast cancer; IκBα; NF-κB; Negative feedback loop; PIMREG.

MeSH terms

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

Substances

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