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

Zhigang Yu,Yuxin Cui,Jianqiao Cao,Yizi Cong,Tracey A Martin,Shiguang Zhu,Guangdong Qiao,Haidong Zou,Wenguo Jiang

doi:10.21147/j.issn.1000-9604.2020.05.02

Zhigang Yu, Yuxin Cui + Show 7 more

Open Access

https://doi.org/10.21147/j.issn.1000-9604.2020.05.02

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Abstract

ObjectiveAlthough 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.MethodsTim-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. ResultsIn 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-3low 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. ConclusionsTim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.

Highlights

Breast cancer is the most frequently diagnosed malignancy and the main cause of cancer-associated mortality in women [1]
Gene expression levels of T-cell immunoglobulin and mucin-domain containing molecule3 (Tim-3) were analysed in breast cancer (n=1,097) and normal tissue (n=114) from TCGA BRCA datasets
Tim-3 was overexpressed in breast cancer compared with normal tissues (p

Summary

Introduction

Breast cancer is the most frequently diagnosed malignancy and the main cause of cancer-associated mortality in women [1]. T-cell immunoglobulin and mucin-domain containing molecule-3 (Tim-3), known as hepatitis A virus cellular receptor 2 (HAVCR2), is a negative immune checkpoint molecule expressed on a variety of immune cells including T-cells [4], dendritic cells [5] and macrophages [6]. Evidence suggests that resistance to anticytotoxic T-lymphocyte-associated antigen 4 or anti-programmed death-1 (PD-1)/PDligand 1 (PD-L1) inhibitors is compensated by upregulation of additional immune checkpoints, including Tim-3 [10]. PD-1 and Tim-3 co-blockade resulted in a significant survival advantage in a murine lung cancer model [11]. These findings support the view that Tim-3 may be a potential target for tumour therapy

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