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.

ISG12a promotes immunotherapy of HBV-associated hepatocellular carcinoma through blocking TRIM21/AKT/β-catenin/PD-L1 axis

“…The further study based on TCGA database figured out the role of ISG12a as a malignant transformation regulator and a prognostic factor in HBV-associated HCC, which may be mechanically explained by the upregulated p -AKT, p -mTOR, and PD-L1 levels. 35 , 36 Furthermore, administration of wild-type NK-92 cells in NCG mice dramatically suppressed the growth of tumors formed by ISG12a-silenced of HBV-infected HLCZ01 cells. Actually, the depressed cytolytic activity and reduced number of NK cells are indicators of malignant transformation and poor prognosis of HCC.…”

The current status and future of PD-L1 in liver cancer

“…More importantly, MTDH ASO improved anti-PD-1 response in PD-1-treated malignancies and increased infiltration of cytotoxic T cells ( 94 ). PD-L1 up-regulated serum and glucocorticoid kinase 2 (SGK2), activated SGK2/β-catenin signaling pathway, and promoted the expansion of HCC cell epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) ( 95 ). Synoviolin (SYVN1) regulated FoxO1 ubiquitination and stimulated β-catenin nuclear translocation, promoting PD-L1-mediated liver cancer metastasis and immune escape ( 96 ).…”