The Mechanism Of TIPE2 In The Development And Progression Of Clear Cell Renal Cell Carcinoma

Objective Researches found that TIPE2 unusually expressed in a range of tumors,but the relationship between TIPE2 and Clear cell renal cell carcinoma(cc RCC)is still unclear.This study using bioinformatics analysis and experiment to explore the relationship between the TIPE2 with cc RCC and its possible mechanism.Methods⑴ The ccRCC patient’s TIPE2 expression spectrum and their clinical data are downloaded from the public database,and online database is used to calculate TIPE2 expressed in cc RCC.Then,We confirm that the expression of TIPE2 in cc RCC patiens by Western Blot and immunohistochemistry.The relationship of TIPE2 expression and the overall survival of cc RCC is estimated by Kaplan-Meier survival analysis.⑵ Through the correlation analysis to excavate the related genes of TIPE2.The related genes of TIPE2(EP3、EBI3)are verified by experiments in cc RCC.The function of TIPE2 are explored by GO and KEGG.⑶ To evaluate each cc RCC patient’s immune cells infiltration and immune function by ss GESA algorithm.To further evaluate the differences of immune cells infiltration and function in the high and low level of TIPE2.To calculate the immune score and the stomal score of cc RCC by ESTIMATE algorithm and evaluate the differences of tumor microenvironment in the high and low levels of TIPE2.Results⑴ TCGA shows that the expression of TIPE2 is higher than normal group in cc RCC tumor tissue(P<0.0001),and is consistent with the experimental results.High expression of TIPE2 is associated with low survival rate in cc RCC(P=7.63e-03).Otherwise,TIPE2 expression is significantly associated with higher RCC-Stage(P=0.0027)and higher histological grade(P=0.0004).⑵ Through the correlation analysis to excavate the related genes of TIPE2.And Western Blot and immunohistochemistry show that EP3,EBI3 expressed in cc RCC are consistent with this study results.Enrichment analysis of GO,KEGG pathway of TIPE2 showed that TIPE2 were positively involved in T cell activation,Regulation of lymphocyte activation,Positive regulation of leukocyte activation,Response to interferon-gamma,T cell receptor complex,Plasma membrane receptor complex,Cytokine receptor activity and Peptide antigen binding in GO,it also positively involved in Ctyokine-cytokine receptor interaction,Antigen processing and presentation,Natural killer cell mediated cytotoxicity,Th17 cell differentiation,Th1 and Th2 cell differentiation,JAK/STATs signaling pathway and NF-k B signaling pathway in KEGG.Otherwise,it were negatively involved in Hormone-mediated signaling pathway,Response to peptide hormone,Steroid hormone receptor activity,Nuclear receptor activity in GO.And,it were negatively involved in Regulation of actin cytoskeleton,Rap1 signaling pathway,Erb B signaling pathway,Ras signaling pathway,Estrogen signaling pathway,PI3K/AKT signaling pathway,MAPK signaling pathway and Axon guidance.⑶ The results of ss GESA and ESTIMATE showed that TIPE2 changes tumor microenvironment in cc RCC.TIPE2 affects the infiltration of Dendritic cells,B cells,CD8 T+ cells,Macrophages,Natural killer cells,Neutrophils,T helper cells and Treg cells in cc RCC.Also,TIPE2 play a role on cc RCC through immune pathways,such as The process of antigen presenting,Cytokine activation,T cell activity,Interferon response.Moreover,we found that TIPE2 is markedly correlated with the immune score and the stomal score in cc RCC.Conclusions⑴ TIPE2 overexpression is associated with the tumor progression and prognosis of patients with cc RCC.⑵ TIPE2 may be participate in the occurrence and development of cc RCC through the regulation of immune cells infiltration and immune pathways.