首页|Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression

Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression

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Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been established.Methods:Kaplan-Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients.The effect of neutrophils on lung cancer was determined using the Transwell migration assay,a proliferation assay,and a murine tumor model.Gene knockdown was used to determine poly ADP-ribose polymerase(PARP)-1 function in lung cancer-educated neutrophils.Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9(MMP-9).Immunoprecipitation coupled to mass spectrometry(IP/MS)was used to identify the proteins interacting with PARP-1.Co-immunoprecipitation(Co-IP)was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase(ALOX5).Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.Results:An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients(P<0.001).Neutrophil activation promoted lung cancer cell invasion,migration,and proliferation in vitro,and murine lung cancer growth in vivo.Mechanistically,PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification(PARylation).Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production,and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.Conclusion:We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression,which exacerbates lung cancer progression.

Lung cancerneutrophilsPARP-1ALOX5MMP-9

Lulu Han、Yuxin Chen、Nan Huang、Xiaowan Zhou、Yanfang Lv、Huizhong Li、Dafei Chai、Junnian Zheng、Gang Wang

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Cancer Institute,Xuzhou Medical University,209 Tongshan Road,Xuzhou 221004,China

Center of Clinical Oncology,The Affiliated Hospital of Xuzhou Medical University,99 West Huaihai Road,Xuzhou 221002,China

Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,Xuzhou Medical University,209 Tongshan Road,Xuzhou 221004,China

Department of Oncology,Suzhou Xiangcheng People's Hospital,Suzhou 215131,China

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National Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaJiangsu Province Social Development Key ProjectsJiangsu Province Social Development Key ProjectsXuzhou Medical University Excellent Talent Research Startup FundJiangsu Province Capability Improvement Project through Science,Technology and EducationChina Postdoctoral Science Foundation

2018YFA090090082273334822031728187186981400055BE2020641BE2020640RC20552157CXZX2022342023M732970

2024

10.20892/j.issn.2095-3941.2023.0248

癌症生物学与医学(英文版)
中国抗癌协会

癌症生物学与医学(英文版)

CSTPCD
影响因子：1.07
ISSN：2095-3941
年,卷(期)：2024.21(2)
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