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
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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