人乳头瘤病毒介导CXCL8-NETs轴与宫颈癌侵袭转移的关系研究OA

Objective:To investigate the mechanism of neutrophil extracellular traps(NETs)in human papillomavirus(HPV)-associated cervical cancer and its clinical significance.Methods:Based on the GSE151666 dataset(10 HPV-negative and 58 HPV-positive cervical cancer samples)to mine HPV-associated cervical cancer immune-associated pathways,67 fresh speci-mens(5 normal cervixes,5 HPV-negative cervical carcinomas,and 57 HPV-positive cervical carcinomas tissues)surgically re-sected between April 2017 and January 2022 from the Cancer Hospital of Xinjiang Medical University,50 paraffin tissue speci-mens,and 20 serum specimens were selected.Immunohistochemistry was applied to detect the relevant markers of NETs and ana-lyzed the relationship between NETs and clinicopathological features of cervical cancer.The key molecules that promote the forma-tion of NETs in HPV-associated cervical cancer were screened by transcriptome sequencing and validated by ELISA,Western blot,and TCGA-CESC dataset.Results:NETs formation pathway ranked among the Top 10 HPV-associated cervical cancer immune-related pathways.Neutrophil infiltration marker CD66b and NETs marker MPO were highly expressed in cervical cancer tissues(P＜0.05)and were higher in HPV-positive cervical cancer tissues,which were co-localized in mesenchymal neutrophils.High expression of Cit-H3 was associated with large tumor diameter,deep myometrial infiltration,and poor differentiation,and high expression of MMP9 was associated with deep myometrial infiltration(P＜0.05).Transcriptome sequencing revealed that chemokines CXCL8,CXCL10,and CXCL11 were differentially expressed genes,and serum CXCL8 levels,quantified by ELI-SA,were 99.39,131.71,and 257.57 pg/mL in control,HPV-negative,and HPV-positive cervical cancer patients,respectively,with statistically significant differences among the groups(P＜0.05).In vitro experiment confirmed that CXCL8 could promote the generation of neutrophil NETs.CXCL8 was correlated with cervical cancer immune microenvironment neutrophil infiltration and chemoresistance.Conclusion:Levels of NETs were significantly upregulated in HPV-positive cervical cancer tissues,and the high expression was closely associated with malignant progression features such as increased tumor diameter,deep muscular infil-tration,and low differentiation.CXCL8 may be involved in the regulation of NETs production as a core molecule,and targeting the CXCL8-NETs axis may become a novel intervention strategy for attenuating aggressive phenotypes of HPV-associated cervi-cal cancer.