Neutrophil extracellular traps induced by interleukin 8 via CXCR1/2 promote the progression of gastric carcinoma through transcription factor IIB-related factor 1 and cyclin

Neutrophils constitute a significant portion of the immune cells present within the tumor microenvironment.Evidence generated by our group has confirmed neutrophils to be an adverse independent prognostic factor affecting the disease-free survival of gastric carcinoma(GC)patients.1 Neutrophil extracellular traps(NETs),protein-covered DNA webs that interact with tumor cells in the tumor microenvironment,were detected in GC tissues and found to clinically associated with disease progression in our previous study.2 NETosis could be mediated by a series of agonists,such as interleukin 8(IL-8).3 However,the mechanism of IL-8 in the progression of GC occurs via NETs remains unclear.In this study,we identified that IL-8-mediated NETosis can promote the proliferation,migration,and invasion of GC cells in vitro,which can be abrogated by NET degradation through deoxyribonucleaseI(DNase I)or IL-8 suppression through neutralizing antibodies.Disruption of NETs by DNase I or blockade of the IL-8-CXC chemokine receptor 2(CXCR2)axis could result in growth retardation in mouse models.We also confirmed that NETs may influence the biological behavior of GC cells by up-regulating the expression of transcription factor IB-related factor 1(BRF1)and cyclin p21/p27.

High VHL Expression Reverses Warburg Phenotype and Enhances Immunogenicity in Kidney Tumor Cells

Clear cell renal cell carcinoma(ccRCC)is a frequently occurring renal cancer.The Von Hippel-Lindau disease tumor suppressor VHL,a known tumor suppressor gene,is frequently mutated in about 50%of patients with ccRCC.However,it is unclear whether VHL influences the progression of ccRCC tumors expressing wild-type VHL.In the present study,we found that higher expression of VHL was correlated with the better disease-free survival(DFS)in ccRCC patients using The Cancer Genome Atlas(TCGA)datasets.We revealed that VHL overexpression in ccRCC cells inhibited epithelial-mesenchymal transition(EMT),sterol regulatory elementbinding protein 1(SREBP1)-regulated triglyceride synthesis,and cell proliferation.Proteomic analysis provided us a global view that VHL regulated four biological processes,including metabolism,immune regulation,apoptosis,and cell movement.Importantly,we found that VHL overexpression led to up-regulated expression of proteins associated with antigen processing and interferonresponsive proteins,thus rendering ccRCC cells more sensitive to interferon treatment.We defined an interferon-responsive signature(IRS)composed of ten interferon-responsive proteins,whose m RNA expression levels were positively correlated with DFS in ccRCC patients.Taken together,our results propose that the subset of ccRCC patients with high VHL expression benefit from immunotherapy.