Activation of G Protein-Coupled Estrogen Receptor Induces p53 and ADAMTS1 to Inhibit Tumor Growth and Suppress Liver Cancer Metastasis

<b>Background/Objectives</b>: Liver cancer is a common cause of cancer-related deaths among men and women globally. A disintegrin and metalloproteinase with thrombospondin motif 1 (ADAMST1) has been associated with various cancers, including prostate, esophageal, renal, and breast cancers. However, its role in liver cancer remains unclear. The aim of this study was to investigate the relationship between G protein-coupled estrogen (GPER) activation via its agonist, G1, and ADAMTS1 in suppressing liver cancer metastasis. <b>Methods</b>: Following preliminary assessment of Hep3B, Huh7, and SK-Hep-1 cells, SK-Hep-1 cells were selected owing to their elevated GPER expression and reduced cell viability. Cells were subjected to flow cytometry, RNA sequencing, and proteomics analyses. We established an SK-Hep-1 xenograft model for in vivo analysis. <b>Results</b>: We observed G1-induced G2-M phase cell cycle arrest, increased p53 and p21, and decreased cell cycle-related factors. In vivo, G1 significantly inhibited tumor growth and increased p53 protein expression. ADAMTS1, a metastasis regulator, was significantly upregulated by G1. G1 reduced the proliferating cell nuclear antigen and increased E-cadherin expression in SK-Hep-1 cells and in vivo. Tumor invasion was reduced with G1 and ADAMTS1 expression. In vivo, G1 reduced liver metastasis, increased E-cadherin, and decreased vimentin and proliferating cell nuclear antigen in primary tumor tissues and increased ADAMTS1 at the tumor edge. <b>Conclusions</b>: GPER agonists, such as G1, show potential for suppressing liver cancer progression and metastasis.