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

Abstract

virus cellular receptor 2 (HAVCR2), is a negative immune checkpoint mole cule expressed on a variety of immune cells including T cells [5], dendritic cells [6], and macrophages [7]. Accumulating evidence demonstrate that Tim-3 can reduce cell proliferation, decrease the production of effective cytokines and increase apoptosis of effector T cells, through interaction with its ligands including galectin-9, high mobility group protein B1 (HMGB1), carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM-1) and phosphatidylserine [8,9].Tim-3 is now considered as a critical mediator in cancer pro gression and attracts considerable attention as a therapeutic target. Blocking Tim-3 indeed shows some promising results in multiple preclinical cancer models [10]. More importantly, there is evidence suggesting that resistance to anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) or anti-PD-1/PD-L1 inhibitors is partially by compensatory upregulation of additional immune checkpoints including Tim-3 [11]. And co-blockade of PD-1 and Tim-3 shows a significant survival advantage in a lung cancer mouse model [12]. These findings support the view that Tim-3 may be a potential target for tumour therapy.Interestingly, Tim-3 is not only expressed on immune cells but also overexpressed on many types of malignant tumours. In vitro findings revealed that Tim-3 promoted metastasis of esophageal squamous cell carcinoma (ESCC) by inducing epithelial-mesenchymal transition (EMT) via the Akt/GSK-3/Snail signalling pathway. Tim-3 knockdown markedly inhibited proliferation, migration, and invasion of ESCC cell lines [13]. Additionally, Interfering Tim-3 expression can significantly suppress osteosarcoma cell proliferation and metastasis via the NF-κB/Snail signalling pathway and EMT [14].Recently, a study in liver cancer indicated that tumour cell-intrinsic Tim-3 promotes cell proliferation via the NF-κB/IL-6/STAT3 cascade signalling axis [15]. Clinically, The ectopic expression of Tim-3 in tumour cells were correlated with more advanced pathologic T classification in non-small-cell lung carcinoma [16], lymph-vascular invasion in gastric cancer [17], lung metastasis in clear cell renal cell carcinoma [18], and lymphatic metastasis in colon cancer [9]. A meta-analysis revealed that higher expression of Tim-3 in solid tumours had significantly shorter overall survival [19]. Therefore, Tim-3 has been depicted as a prognostic indicator for those cancer patients. But contradictory results were also reported in terms of the role of Tim-3. Down-regulated Tim-3 promotes invasion and metastasis

Calcium-Binding Protein S100P Promotes Tumor Progression but Enhances Chemosensitivity in Breast Cancer

“…The authors give great thanks to the technical assistance from the staff of the Cardiff China Medical Research Collaborative (CCMRC), Cardiff University and the Department of Pathology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University. The similar manuscript (mainly method section) has been released as a preprint at ( https://www.researchsquare.com/article/rs-12890/v2 , doi: 10.21203/rs.2.22315/v2), Cong et al ( 50 ).…”