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

AbstractProgrammed 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.