A novel candidate tumor biomarker progestin and adipoQ receptor 3 regulates cell metastasis through transforming growth factor-β pathway in hepatocellular carcinoma.

OBJECTIVE: Progestin and adipoQ receptor 3 (PAQR3) have been identified as a potential tumor suppressor in hepatocellular carcinoma (HCC), yet its role in metastasis remains unclear. This study examined PAQR3 expression in primary HCC and its regulation of cell metastasis and ferroptosis through the transforming growth factor-b (TGF-b) pathway. MATERIAL AND METHODS: PAQR3 expression in HCC tissues was evaluated by immunohistochemistry, while western blotting (WB) and quantitative real-time polymerase chain reaction were used to assess its levels in HCC cells. Cell migration and invasion were analyzed using Transwell and wound-healing assays. WB was employed to measure epithelial-mesenchymal transition-related proteins. Ferroptosis was evaluated by measuring lipid peroxidation, iron accumulation, reactive oxygen species (ROS) levels, and the expression of ferroptosis-related proteins. RESULTS: PAQR3 expression was significantly downregulated in HCC tissues and may serve as a prognostic marker (P < 0.001). PAQR3 overexpression suppressed HCC cell migration and invasion, elevated ROS, Fe(2+), and lipid peroxidation, downregulated GPX4 and SLC7A11, and upregulated ACSL4, thereby promoting ferroptosis (P < 0.001). In addition, PAQR3 overexpression reduced TGF-b1, p-Smad3, and p-Smad2 (P < 0.001), while increasing Smad3 and Smad2, indicating suppression of the TGF-b pathway. CONCLUSION: These findings suggest that PAQR3 inhibits metastasis and induces ferroptosis in HCC through TGF-b pathway regulation.