Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin
Autor: | Yuan Cheng, Xuejiao Han, Qingfang Li, Fei Mo, Xiawei Wei, Yuquan Wei, Houhui Shi, Siyuan Chen |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Cancer Research Lung Neoplasms Neutrophils Gene Expression Apoptosis Lymphocyte Activation Receptors Interleukin-8B Mice 0302 clinical medicine Tumor Microenvironment Molecular Targeted Therapy medicine.diagnostic_test Drug Synergism hemic and immune systems Middle Aged respiratory system Prognosis lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunohistochemistry medicine.anatomical_structure Neutrophil Infiltration Oncology 030220 oncology & carcinogenesis Molecular Medicine Adenocarcinoma Female Lung cancer medicine.drug Adult Epithelial-Mesenchymal Transition T cell T cells Antineoplastic Agents Biology SB225002 lcsh:RC254-282 Flow cytometry 03 medical and health sciences Lymphocytes Tumor-Infiltrating In vivo Cell Line Tumor medicine Animals Humans Aged Cell Proliferation Neoplasm Staging Cisplatin CXCR2 Research Cancer medicine.disease respiratory tract diseases Disease Models Animal 030104 developmental biology Cancer research Biomarkers |
Zdroj: | Molecular Cancer, Vol 20, Iss 1, Pp 1-21 (2021) Molecular Cancer |
ISSN: | 1476-4598 |
Popis: | Background Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear. Methods Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, β-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation. Results The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients’ prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-β. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8+ T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration. Conclusions Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2. |
Databáze: | OpenAIRE |
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