A protein complex of LCN2, LOXL2 and MMP9 facilitates tumor metastasis in esophageal cancer.

Abstract

During malignant tumor 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 remodeling. 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 esophageal squamous cell carcinoma (ESCC) cells, as well as tumor growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumor growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumor 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 signaling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumor progression through multiple mechanisms, and could be a potential therapeutic target.