The Relationship Between Nuclear Receptor Expression And Prognosis Of Clear Cell Renal Carcinoma And Mechanism Of Regulation To Sunitinib Resistance

Objective: 1)To analyze the relationship between the expression of nuclear receptor and prognosis of ccRCC.2)To explore the regulatory mechanism and related signaling pathways of nuclear receptor in RCC.Methods: 1)role of NR and clinical characteristic in predicting ccRCC patient outcomes were determined by using The Cancer Genome Atlas(TCGA)ccRCC dataset.2)Statistical analyze the expression pattern of nuclear receptor in sunitinib treated or untreated ccRCC were determined by using GEO(GSE65615)ccRCC dataset and further screening and validation of nuclear receptor that related to sunitinib resistance by using RT-PCR and Western Blot in vitro and vivo.3)To study the mechanism of PPARα regulatation role in ccRCC to sunitinib resisitance and further explores the molecular mechanism of signaling pathway related to its regulation used by The overexpression and low expression techniques of lentivirus.Results: 1)Age,tumor size,lymph node metastasis,tumor staging and nuclear receptor as well as AR,NR0B1,NR1D2,NR1I2,NR3C2,NR5A1,NR6A1,PPARα,and THRB were significantly different in survival prognosis(P<0.05).2)Statistical analysis of mRNA expression levels from the GEO(GSE65615)database and RT-PCR,Western Blot and immunohistochemical results showed that PPARα was involved in the drug resistance process of the ccRCC.CCK8 test and IC50 indicated that knock down of PPARαinhibited the proliferation,upregulation of drug sensitivity and the inhabited growth of the renal cell lines(786-0,Caki-1 and A498)in vitro.3)upregulation of PPARα induced NF-κB p65 expression and activity,while downregulation of PPARα decreased its expression and activity and the result tested in tissue specimens.Further indicated that inhibition of the NF-κB signaling pathway leads to increased efficacy of sunitinib treatment and that PPARα modulates sunitinib sensitivity synergistically with NF-κB signal inhibition.Conclusions: In this study,we analyzed the biological information ofthe gene expression of ccRCC in TCGA database and screened the nuclear receptor markers with clinical prognostic value.In our study also showed that PPARα plays a role in sunitinib resistance ccRCC,downregulation of PPARα lead to reduced cell viability and increased sensitivity of sunitinib resistance ccRCC lines In vitro and vivo.Further study evaluated that PPARα mediates sunitinib resistance via NF-κB activation in ccRCC.