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; Wenguo Jiang; Zhigang Yu

doi:10.21147/j.issn.1000-9604.2020.05.02

Tim-3 promotes cell aggressiveness and paclitaxel resistance through NF-κB/STAT3 signalling pathway in breast cancer cells

Chin J Cancer Res. 2020 Oct 31;32(5):564-579. doi: 10.21147/j.issn.1000-9604.2020.05.02.

Authors

Yizi Cong^{1

2}, Yuxin Cui³, Shiguang Zhu², Jianqiao Cao², Haidong Zou², Tracey A Martin³, Guangdong Qiao², Wenguo Jiang³, Zhigang Yu¹

Affiliations

¹ Department of Breast Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
² Department of Breast Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264001, China.
³ Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.

PMID: 33223752
PMCID: PMC7666787
DOI: 10.21147/j.issn.1000-9604.2020.05.02

Abstract

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-κB/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.

Keywords: Breast neoplasm; aggression; chemoresistance; hepatitis A virus cellular receptor 2; tight junction.