The Role And Mechanism Of PKCε In Renal Clear Cell Carcinoma Progression And Immune Regulation

Background:Renal cell carcinoma(RCC)is a malignant tumor of urinary system originating in tubular epithelium of the kidney.It has more patients in Western countries,with an increasing number of cases in our country as well.The typical histological subtype of renal cell carcinoma is kidney clear cell carcinoma,abbreviated as KIRC.Most KIRC patients have a poor prognosis and are resistant to chemotherapy and radiotherapy.Therefore,the search for new therapeutic targets and prognostic markers of KIRC will provide an important basis for the treatment and prognosis of KIRC patients.Protein kinase C(PKC)belongs to the serine/threonine kinase family and PKC epsilon belongs to novel PKC.Prkce encodes PKCs.Prkce has been known to be an oncogene in epithelial cells and fibroblasts.There is also some evidence proves that PKCε plays a vital role in promoting tumor cell invasion and metastasis.PKC has also been found that it was associated with chemotherapy resistance.Meanwhile,PKCs was found to be down-regulated in transformed mesenchymal cells.Though PKCs abnormally expressed in KIRC samples and associated with Fuhrman grade and T stage,the prognostic value and mechanism of abnormal expression of PKCs has not been fully investigated.Objectives:To investigate the mechanism of the abnormal expression of PKCεin KIRC and the clinical correlation between PKCε expression and the immune cell infiltration in KIRC.Methods:First,we used a variety of databases,including TCGA,GTEx,and GEO,to assess the correlation between PKCε expression and malignancy of KIRC patients with various pathological features.Second,Kaplan-Meier plotter analysis and univariate and multivariate Cox analysis were used to assess the association between PKCε and clinicopathologic variables and prognosis.Next,the function of PKCε in KIRC was analyzed with CancerSEA.Then,PKCε was further overexpressed to see its effects on the proliferation,invasion and migration ability of KIRC cells in vitro.Next,the methylation level obtained from UALCAN,DiseaseMeth,CCLE,LinkedOmics and MEXPRESS are used to study the relationship between PKCε expression and PKCε methylation level.We also predicted the upstream potential miRNA using Starbase,to explore the mechanism of low expression of PKCε in KIRC.Finally,we analyzed the effect of PKCε on KIRC immune cell infiltration and the correlation of related immune cells with immune checkpoint and prognosis.Results:(1)PKCε is down-regulated in renal clear cell carcinoma,and the decreased expression of PKCε was negatively correlated with pathological progression.(2)Decreased PKCs expression was associated with poor prognosis of KIRC.(3)PKCε was negatively correlated with the proliferation,invasion and migration ability of KIRC cells.(4)The decreased expression of PKCε may be related to the high methylation level of PKCε promoter.(5)hsa-miR-21-5p may be the most potential regulatory miRNA of PKCε in KIRC.(6)Low expression of PKCε is associated with decreased anticancer immune infiltration in the KIRC microenvironment.(7)PKCε was negatively correlated with immune checkpoint.(8)Decreased PKCε expression may affect the prognosis of KIRC patients.Conclusion:In conclusion,PKCs may influence the prognosis of KIRC patients by regulating the immunoinfiltrating of KIRC.Besides,PKCε may be a novel prognostic biomarker and a new therapeutic target for KIRC.