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A protein complex of LCN2, LOXL2 and MMP9 facilitates tumour metastasis in oesophageal cancer.

Authors
  • Xia, Qiaoxi1, 2
  • Du, Zepeng2, 3
  • Chen, Mantong1
  • Zhou, Xiao2
  • Bai, Wenjing1
  • Zheng, Xiaoqi1
  • Lin, Ling1
  • Zhao, Yan2
  • Ding, Jiyu1
  • Wu, Zhisheng1
  • Zou, Haiying1
  • Wang, Shaohong3
  • Xu, Liyan4
  • Li, Enmin1
  • Wu, Bingli1
  • 1 Department of Biochemistry and Molecular Biology, Shantou University Medical College, China. , (China)
  • 2 Central Laboratory, Shantou Central Hospital, China. , (China)
  • 3 Department of Pathology, Shantou Central Hospital, China. , (China)
  • 4 Institute of Oncologic Pathology, Shantou University Medical College, China. , (China)
Type
Published Article
Journal
Molecular Oncology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2023
Volume
17
Issue
11
Pages
2451–2471
Identifiers
DOI: 10.1002/1878-0261.13529
PMID: 37753805
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodelling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of oesophageal squamous cell carcinoma (ESCC) cells, as well as tumour growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumour growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumour cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican-1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3β signalling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumour progression through multiple mechanisms and could be a potential therapeutic target. © 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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