Abstract
As a negative immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain containing molecule-3 (Tim-3) has been found to serve a crucial role in immune escape and tumour progression. Previous studies have reported that Tim-3 is important to endothelial cells and it has also been demonstrated to be involved in numerous types of human diseases, including melanoma, lymphoma, rickettsial infection and atherosclerosis; however, its exact mechanism of action remains largely unknown. In the present study, Tim-3 was overexpressed in vascular endothelial human lung microvascular endothelial cells (HMVECs) and human umbilical vein endothelial cells (HUVECs), and in vitro assays were used to determine that Tim-3 promoted cell proliferation, migration, invasion and tube formation through activating cyclin D1 (CCND1), Ras homolog gene family member A and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2). Additionally, Tim-3 decreased tight junction (TJ) formation and the transepithelial resistance (TER) of endothelial cells by decreasing the expression levels of TJ protein 2, Occludin and claudin 1 (CLND1). In conclusion, these findings suggested that Tim-3 may exert a positive role in angiogenesis and a negative role in TJ formation in vascular endothelial cells, which may provide novel strategies for the treatment of Tim-3-associated diseases.
Highlights
The discovery that T-cell immunoglobulin and mucin family molecules are associated with numerous types of disease, including allergy, autoimmunity [1] and cancer [2], has attracted increasing attention in recent years
human lung microvascular endothelial cell (HMVEC) and human umbilical vein endothelial cell (HUVEC) were stably transfected with full-length Tim-3 overexpression (Tim-3 OE) plasmid or empty vector [Scramble (Scr)] and the expression levels of Tim-3 in the two cell lines were analysed using reverse transcription-quantitative PCR (RT-qPCR) and Western blotting
Tim-3 expression levels were significantly increased in Tim-3 OE cells compared with the Scr and wildtype cells at both the mRNA and protein levels (Figure 1A), which confirmed that the Tim-3 OE plasmid was successfully transfected to the cells
Summary
The discovery that T-cell immunoglobulin and mucin family molecules are associated with numerous types of disease, including allergy, autoimmunity [1] and cancer [2], has attracted increasing attention in recent years. Tim-3 is overexpressed in several types of solid tumours [8,9] and the ectopic expression of Tim-3 in tumour cells has been associated with a more advanced pathological T-cell classification [10], lymph-vascular invasion [11], lung metastasis [12] and lymphatic metastasis [13]. A meta-analysis study revealed that increased expression levels of Tim-3 in solid tumours predicted a significantly shorter overall survival [2]; Tim-3 is suggested to serve as a prognostic indicator for patients
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