Protein tyrosine phosphatase receptor type delta (PTPRD) suppresses the expression of PD-L1 in human hepatocellular carcinoma by down-regulating STAT3

BACKGROUND: Protein tyrosine phosphatase receptor type delta (PTPRD) is a tumor suppressor that is often inactivated in hepatocellular carcinoma (HCC). However, the mechanisms of how PTPRD inhibits HCC are not well understood. Programmed cell death ligand 1 (PD-L1), an immune checkpoint, plays a seminal role in the regulation of carcinogenesis of HCC. The sustained activation of STAT3 is closely related to PTPRD deletion and PD-L1 overexpression; however, whether there is a relationship between PTPRD and PD-L1 expression in HCC has not been investigated. This study aims to investigate the relationship between PTPRD and PD-L1 in HCC samples and illuminate potential new molecular mechanisms of PTPRD effects on PD-L1 in HepG2 cells. METHODS: We collected 16 pairs of tumorous tissues and adjacent normal tissues from HCC patients. The mRNA and protein expression levels of PTPRD and PD-L1 in the HCC tissues were detected by RT-PCR and Western blot analysis. Next, Spearman’s correlation analysis was performed to evaluate the relationship between PTPRD and PD-L1. Then, we transfected the overexpressed or knocked-down PTPRD genes into the HepG2 cell line, and the effects of PTPRD on PD-L1 in HCC cells were evaluated. The activity from the STAT3 and p-STAT3 in the HepG2 cells transfected with PTPRD gene overexpression and knockdown was determined by Western blotting tests. RESULTS: The expression of PTPRD was significantly down-regulated in the HCC tissues compared with the adjacent control tissues; however, PD-L1 was significantly higher in the HCC tissues. There was a negative correlation between PTPRD and PD-L1 expression in the HCC tissues. PTPRD over-expression significantly inhibited PD-L1 expression; meanwhile, PTPRD depletion promoted PD-L1 expression in the HepG2 cells. Furthermore, PTPRD over-expression significantly inhibited the expression of STAT3 and p-STAT3, while PTPRD depletion promoted these cytokines. Our studies revealed that PTPRD repressed PD-L1 expression in the HepG2 cells, which might occur via the STAT3 pathway. CONCLUSIONS: The results from our study show that PTPRD and PD-L1 are negatively correlated in HCC tissues. PTPRD suppresses PD-L1 expression in HepG2 cells by down-regulating STAT3. These findings are expected to become a new target for the immunotherapy of HCC.