The EGFR‐P38 MAPK axis up‐regulates PD‐L1 through miR‐675‐5p and down‐regulates HLA‐ABC via hexokinase‐2 in hepatocellular carcinoma cells

Abstract

BackgroundImmunotherapy has been shown to be a promising strategy against human cancers. A better understanding of the immune regulation in hepatocellular carcinoma (HCC) could help the development of immunotherapy against HCC. The epidermal growth factor receptor (EGFR) signaling is frequently activated in HCC and plays important roles in tumorigenesis. However, its role in HCC immunity is still largely unknown. This study aimed to investigate the impact of EGFR signaling on programmed death‐ligand 1 (PD‐L1) and human leukocyte antigen class‐I (HLA‐I) expression in HCC cells and its underlying mechanisms.MethodsThe expression of phosphorylated EGFR (p‐EGFR), PD‐L1, and HLA‐I (HLA‐ABC) in HCC specimens was detected by immunohistochemistry, and their correlations were analyzed. PD‐L1 and HLA‐ABC expression in EGFR‐activated HCC cells were detected by quantitative real‐time PCR, Western blotting, and flow cytometry, and T cell‐mediated lysis was performed to test the immunosuppressive effects of PD‐L1 and HLA‐ABC alterations in HCC cells. Furthermore, the underlying mechanisms of EGFR activation‐induced PD‐L1 up‐regulation and HLA‐ABC down‐regulation were explored by animal experiments, luciferase reporter assay, and gene gain‐ and loss‐of‐function studies.Resultsp‐EGFR was positively correlated with PD‐L1 and negatively correlated with HLA‐ABC expression in HCCs. EGFR activation by its ligand EGF up‐regulated PD‐L1 and down‐regulated HLA‐ABC in HCC cells, which was functionally important and could be abolished by the EGFR inhibitor, gefitinib, both in vitro and in vivo. Mechanistically, enhanced P38 mitogen‐activated protein kinase (MAPK) activation down‐regulated microRNA‐675‐5p (miR‐675‐5p) and up‐regulated glycolysis‐related enzyme hexokinase 2 (HK2); miR‐675‐5p down‐regulation enhanced the stability of PD‐L1 mRNA probably via the 3’‐untranslated region (3’‐UTR) of PD‐L1 and thereby caused PD‐L1 accumulation, and HK2 up‐regulation enhanced aerobic glycolysis and mediated a decrease in HLA‐ABC.ConclusionsThe EGFR‐P38 MAPK axis could up‐regulate PD‐L1 through miR‐675‐5p and down‐regulate HLA‐ABC via HK2 in HCC cells. Our study reveals a novel signaling network that may cause immune suppression in HCC and suggests that EGFR signaling can be targeted for HCC immunotherapy.

Pharmacoinformatics Analysis Reveal Flavonoids and Diterpenoids from Andrographis Paniculata and Thespesia Populnea as Potential Modulators of Hepatitis B Virus Induced Hepatocellular Carcinoma

“…Similarly, VersicanV1 was also found to enhance EGFR-PI3K-Akt signalling pathway in HCC cells [44]. A recent study by Liu et al [45] demonstrated that, in HCC cells, the EGFR-P38 MAPK axis may up-regulate PD-L1 via miR-675-5p and down-regulate HLA-ABC via HK2 and this might be responsible for the immune suppression in HCC, and they suggest that EGFR signalling might be targeted for HCC immunotherapy. Hence, based on the potential role of EGFR in HCC and also key network hub status in the current study, the phytocompounds were screened against EGFR.…”

MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

“…PD-L1 upregulation in HCC cells can be driven also by the EGFR-P38 MAPK axis, via miR-675-5p [ 73 ]. Interestingly, phospho-EGFR directly correlated with PD-L1 expression and inversely correlated with HLA-ABC in HCC tissues and cell lines.…”

The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer

“…PD-L1 inhibition T-cell function and the activation of EGFR by its ligand can induce the positive regulation of this molecule. In this sense, it has been suggested that the EGFR inhibitor Gefitinib was able to decrease PD-L1 expression and inhibition of T-cell-mediated lysis of liver cancer cells through EGFR activation [ 45 ]. Thus, anti-PD-L1 antibody therapy could be used to decrease immunosuppression in cancer patients with uncontrolled EGFR activation [ 46 ].…”

“…In addition, the expression levels of miR-675-5p differ in different cancers contributing to several functions such as cell proliferation and invasion, as well as metastasis [ 47 , 48 ]; the downregulation of miR-675-5 by p38 MAPK activation provides stability to the PD-L1 RNA through the 3’-UTR region and thus causes PD-L1 accumulation. For this reason, the EGFR/p38 MAPK axis has been involved in the regulation of PD-L1 through miR-675-5p with interesting potential on the immunotherapy of hepatocellular carcinoma that needs more in-depth studies [ 45 ].…”