Programmed death ligand 1 regulates epithelial-mesenchymal transition and cancer stem cell phenotypes in hepatocellular carcinoma through the serum and glucocorticoid kinase 2/β-catenin signaling pathway.

Abstract

Programmed death ligand 1 (PD-L1) plays an important role in the occurrence of hepatocellular carcinoma (HCC). The present study indicated that epithelial-mesenchymal transition (EMT) and induction of cancer stem cell (CSC)-like properties contribute to metastasis of cancers. However, the molecular mechanisms underlying PD-L1 and EMT and CSC phenotypes in HCC remain to be elucidated. Here, we report that PD-L1 regulates not only EMT but also the stem-like transition in liver cancer cells. We observed high PD-L1 expression in CD133+ liver CSCs and CSC-enriched tumor spheres. Altering PD-L1 expression promoted liver CSC phenotypes by increasing the expression of stemness genes, the CD133+ cell population sizes, and the ability to form tumor spheres. Programmed death ligand 1 enhanced HCC cell tumorigenicity and invasion in nude mice. Additionally, PD-L1 overexpression in cells significantly increased cell motility and invasion, as well as the EMT process. Conversely, suppression of PD-L1 in cells had an opposite effect. Prolonged treatment of HCC cells with Akt inhibitor prefosine leads to activation of serum and glucocorticoid kinase 2 (SGK2) and rescued downregulation of PD-L1. Mechanistically, PD-L1 directly interacted with SGK2. Programmed death ligand 1 upregulated SGK2 and activated the SGK2/β-catenin signaling pathway, and promoted EMT and CSC expansion in liver cancer cells, highlighting the role of SGK2 in PD-L1-mediated EMT and CSC phenotypes in liver cancer cells. In conclusion, our findings suggest that PD-L1 activated the SGK2/β-catenin signaling pathway, to induce EMT and acquisition of a stem cell phenotype.