Tim-3 promotes cell aggressiveness and paclitaxel resistance through NF-κB/STAT3 signalling pathway in breast cancer cells
Yizi Cong, Yuxin Cui, Shiguang Zhu, Jianqiao Cao, Haidong Zou, Tracey A. Martin, Guangdong Qiao, Wen G. Jiang, Zhigang Yu
Abstract
<sec><b>Objective</b>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.</sec><sec><b>Methods</b><i>Tim-3</i> gene expression in breast cancer and its prognostic significance were analyzed. Associated mechanisms were then explored <i>in vitro</i> by establishing Tim-3-overexpressing breast cancer cells.</sec><sec><b>Results</b>In a pooled analysis of The Cancer Genome Atlas (TCGA) database, <i>Tim-3</i> 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<sup>low</sup> 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-κB/STAT3 signalling pathway and by regulating gene expression [cyclin D1 (<i>CCND1</i>), <i>C-Myc</i>, matrix metalloproteinase-1(<i>MMP1</i>), <i>TWIST</i>, vascular endothelial growth factor (<i>VEGF</i>) upregulation, concomitant with <i>E-cadherin</i> downregulation). Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression.</sec><sec><b>Conclusions</b>Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.</sec>