The Role And Mechanism Of Orphan Nuclear Receptor Nur77 Regulating PD-L1

The nuclear receptor Nur77(TR3)is encoded by the immediate early gene NR4A1 and plays an important role in immune regulation,tumorigenesis and development.Programmed Death Ligand 1(PD-L1)is a 40 kDa transmembrane protein that is highly expressed in a variety of malignancies and is Closely related to poor prognosis of the tumor.PD-L1 interacts with receptor PD-1,that inhibits the activation and proliferation of immune cells such as NK cells and T cells,and that disrupts and depletes its function,thereby inhibiting its killing of the tumor and promoting tumor immune escape.Although both Nur77 and PD-L1 play an important role in immune regulation,the relationship between them has not been well studied.In this topic,we focused on the regulation of PD-L1 by Nur77.First,we examined the expression of Nur77 and PD-L1 in different breast cancer cells and found a Clear negative correlation between Nur77 and PD-L1 expression.Next,knockdown of Nur77 in MDA-MB-231 cells by siRNA technology revealed that PD-L1 expression was significantly up-regulated,indicating that Nur77 can negatively regulates PD-L1 expression in breast cancer cells.In HeLa cells,PD-L1 expression and mRNA levels were significantly up-regulated by siRNA knockdown or Crispr knockout of Nur77;Overexpression of Nur77,PD-L1 expression was significantly downregulated.To further study the biological function of Nur77-regulated PD-L1,we performed a co-culture experiment of natural killer NK-92 MI cells with HeLa cells,and the results showed that knockdown of Nur77 in HeLa cells can impaired the immune killing effect of natural killer NK-92 MI cells.Given the important role of STAT1 in the regulation of PD-L1,we examined the interaction of Nur77 with STAT1 by co-immunoprecipitation and found that Nur77 and STAT1 have a strong interaction.At the same time,knockdown of Nur77 in HeLa cells revealed a significant increase in the phosphorylation level of STAT1.Thus,it was initially Clarified that Nur77 can negatively regulates the expression of PD-L1 by inhibiting the STAT1 signaling pathway.This study finds an important link between Nur77 and PD-L1,and initially Clarifies the role of Nur77 in the regulation of PD-L1,and reveals the novel role of Nur77 in tumor immunomodulation,and expands the biological function of Nur77.At the same time,this study provides a new idea for the screening of anti-inflammatory and anti-tumor immune drugs,that is,by screening Nur77 regulators to further screen for anti-inflammatory and anti-tumor immune drugs.