Tim-3 Promotes Cell Aggressiveness And Paclitaxel Resistance Through Nf-Kappa B/Stat3 Signalling Pathway In Breast Cancer Cells

Objective: Although T-cell immunoglobulin and mucin-domain containing molecule-3 (Tim-3) has been recognized as a promising target for cancer immunotherapy, its exact role in breast cancer has not been fully elucidated.Methods: Tim-3 gene expression in breast cancer and its prognostic significance were analyzed. Associated mechanisms were then explored in vitro by establishing Tim-3-overexpressing breast cancer cells.Results: In a pooled analysis of The Cancer Genome Atlas (TCGA) database, Tim-3 gene expression levels were significantly higher (P<0.001) in breast cancer tissue, compared with normal tissues. Tim-3 was a prognosis indicator in breast cancer patients [relapse-free survival (RFS), P=0.004; overall survival (OS), P=0.099]. Tim-3 overexpression in Tim-3(low) breast cancer cells promoted aggressiveness of breast cancer cells, as evidenced by enhanced proliferation, migration, invasion, tight junction deterioration and tumor-associated tubal formation. Tim-3 also enhanced cellular resistance to paclitaxel. Furthermore, Tim-3 exerted its function by activating the NF-kappa B/STAT3 signalling pathway and by regulating gene expression [cyclin D1 (CCND1), C-Myc, matrix metalloproteinase-1(MMP1), TWIST, vascular endothelial growth factor (VEGF) upregulation, concomitant with E-cadherin downregulation). Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression.Conclusions: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.