Yizi Cong1,2, Yuxin Cui3, Shiguang Zhu2, Jianqiao Cao2, Haidong Zou2, Tracey A Martin3, Guangdong Qiao2, Wenguo Jiang3, Zhigang Yu1. 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.
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-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. CONCLUSIONS: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.
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-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. CONCLUSIONS: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.
Authors: Smruthi Vijayaraghavan; Merih Guray Durak; Nicole M Kettner; Tuyen Bui; Mehrnoosh Kohansal; Min Jin Ha; Bin Liu; Xiayu Rao; Jing Wang; Min Yi; Jason P W Carey; Xian Chen; T Kris Eckols; Akshara S Raghavendra; Nuhad K Ibrahim; Meghan Sri Karuturi; Stephanie S Watowich; Aysegul Sahin; David J Tweardy; Kelly K Hunt; Debu Tripathy; Khandan Keyomarsi Journal: Clin Cancer Res Date: 2019-03-13 Impact factor: 12.531
Authors: Yunlong Huang; Ran Ruan; Yanxin Fang; Kaiming Wu; Long Yao; Renquan Zhang; Wei He Journal: Int J Mol Med Date: 2021-08-09 Impact factor: 4.101