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

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.

TIM-3 as a Prognostic Marker and a Potential Immunotherapy Target in Human Malignant Tumors: A Meta-Analysis and Bioinformatics Validation

“…Moreover, further TCGA data (n=9491 cases) also confirmed a significant relationship between TIM-3 expression and poor OS, and no relationship between TIM-3 expression and DFS in cancer. TIM-3 may have a function in promoting tumor cell proliferation, migration, and invasion ( 66 , 67 ). TIM-3 facilitates the initiation of tumor and tumor-promoting activities ( 66 , 68 ).…”

“…TIM-3 may have a function in promoting tumor cell proliferation, migration, and invasion ( 66 , 67 ). TIM-3 facilitates the initiation of tumor and tumor-promoting activities ( 66 , 68 ). The interactions between TIM-3 and its ligands inhibit Th1 and Th17 responses and NK cell-mediated cytotoxicity, resulting in immune tolerance ( 68 – 70 ).…”

GFI1 promotes the proliferation and migration of esophageal squamous cell carcinoma cells through the inhibition of SOCS1 expression

“…The STAT3 and NF-κB signaling pathways are two vital intracellular pathways that serve key roles in modulating cell differentiation, proliferation, migration and metabolism (37,38). These pathways are frequently overactivated in various types of cancer, including colorectal, non-small lung and breast cancer, and have been reported to contribute to tumor progression and drug resistance (39)(40)(41). Previous studies have demonstrated that the STAT3 and NF-κB pathways are aberrantly activated during EScc development (17,42,43).…”

The Emerging Role of T-Cell Immunoglobulin Mucin-3 in Breast Cancer: A Promising Target For Immunotherapy

“…Tim-3 overexpression in breast cancer cells promotes cell proliferation, migration, invasion, and tumor-associated tubal formation and enhances chemoresistance to paclitaxel by activating the NF-κB/STAT3 pathway and its downstream genes (cyclin D1, matrix metalloproteinase-1, vascular endothelial growth factor, and E-cadherin). Tim-3 also deteriorates tight junctions by downregulating zona occludens (ZO)-2, ZO-1, and occludin, which further accelerates tumor progression ( 54 ). Another study supported the aforementioned findings by reporting that downregulation of Tim-3 in breast cancer cells inhibited their proliferation, migration, and invasion and promoted their apoptosis ( 20 ).…”