Abstract
Purpose :
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, characterized by a short overall survival after metastasis due to the lack of effective treatments. Previous studies have demonstrated that licorice extracts effectively inhibit tumor progression by suppressing high mobility group box 1 (HMGB1). This study aims to investigate the role and mechanism of HMGB1 in the progression of UM and the effects of licorice extracts on UM.
Methods :
The functions of HMGB1 were predicted based on The Cancer Genome Atlas data. Gene expression modulation was achieved through targeted knockdown using siRNAs and overexpression via transfection with cDNA-inserted plasmids. RNA sequencing (RNA-seq) was performed on UM cell lines. Gene set enrichment analysis (GSEA) was used to predict the enrichment of signaling pathways. Cell proliferation, invasion and apoptosis were assessed by CCK8, colony formation, transwell assays and flow cytometry, respectively. UM cell lines (C918, OCM1A and OMM2.3) were treated with glycyrrhizin (GL), 18β-glycyrrhetinic acid (18β-GA) and diammonium glycyrrhizinate (DG). The level of autophagy was assessed by western blot (WB).
Results :
Elevated HMGB1 expression was correlated with poorer prognosis including death, pathologic classification of epithelial cell and tumor occurrence (p<0.05, 0.01 and 0.01 respectively). Knockdown of HMGB1 suppressed the growth and migration of UM cells (p<0.001), and promoted cell apoptosis (p<0.001). GSEA indicated dysregulation of the autophagy pathway following downregulation of HMGB1. WB confirmed that autophagy was inhibited by HMGB1 knockdown, while HMGB1 overexpression facilitated autophagy. CCK8 revealed that treatment with GL, 18β-GA, and DG effectively inhibited proliferation of UM cells. WB demonstrated that licorice extracts inhibited HMGB1 nucleocytoplasmic translocation and suppressed autophagy induced by HMGB1 overexpression.
Conclusions :
HMGB1 is correlated with tumor invasiveness and a poor prognosis in UM patients by regulating autophagy. Licorice extracts demonstrate potential in inhibiting UM progression by impeding the nucleocytoplasmic translocation of HMGB1 and regulating autophagy processes. This study provides insights into the role and mechanism of HMGB1 in UM and suggests the potential of licorice extracts in the treatment of metastatic UM.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.