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.Ho...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.展开更多
基金supported by the Chinese Ministry of Science and Technology(Grant Nos.2017ZX10201101 and 2014CBA02005)the China Postdoctoral Science Foundation(Grant No.2017M610080)+2 种基金the National Key R&D Program(Grant No.2017YFA0505103)the National Nature Science Foundation of China(Grant No.21877068)the Shandong Science and Technology Committee(Grant No.2018GSF118159)。
文摘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.
