Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide, and the methods for its treatment have shown limited efficacy. There is an urgent need to explore the underlying mechanism that are involved in hepatocarcinogenesis, contributing to find various signal molecular targets for HCC diagnosis, prevention and therapy. Recently, Various studies have illustrated protein tyrosine phosphatase receptor type D (PTPRD) is an important tumor-suppressor gene that is down-regulated in HCC and this downregulation occurs through its promoter hypermethylation. PTPRD is involved in the progression, migration, apoptosis, invasion and immune suppression of HCC. Also, PTPRD participates in several vital cellular signaling pathways, including PTPRD, signal transduction and activation of transcription 3 (STAT3), JAK, PTPRD, β-catenin, TCF, along with the PTPRD-CXCL8 axis, the PTPRD/phosphatidylinositol3-kinase (PI3K)/mammalian target of rapamycin (mTOR), and the PTPRD/ PD-1/programmed death receptor ligand-1 (PD-L1) axis, thus playing an essential role in HCC. Therefore, PTPRD can be considered as a novel therapeutic target for HCC, and PTPRD-targeted therapeutics in combination with methylation inhibitors, immune checkpoint inhibitors and alternative targeted drugs maybe an innovative treatment method for HCC. However, clinical research of PTPRD-targeted therapies in HCC is greatly limited and tremendous efforts are strongly urged to evaluate its clinical performance in HCC. In this review, we summarized the physiological function and the significant effects of PTPRD and performed a comprehensive analysis of PTPRD-targeted strategies for HCC.

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.