Prostaglandin F2 Receptor Negative Regulator Drives Cancer Stemness and Immune Evasion in Hepatocellular Carcinoma cells

Hepatocellular carcinoma (HCC) presents significant therapeutic challenges due to its high propensity for recurrence and metastasis, processes largely mediated by circulating tumor cells (CTCs) that possess unique survival and immune-evasive properties. Prostaglandin F2 receptor negative regulator (PTGFRN) has been previously identified as a diagnostic biomarker for CTCs in HCC. Building upon this, our study elucidates the functional role of PTGFRN in promoting the survival and immune evasion of HCC cells. Using shRNA knockdown in Huh7 and SNU449 HCC cell lines, we demonstrate that PTGFRN is essential for cell migration, invasion, and adhesion to the extracellular matrix. Specifically, PTGFRN silencing led to a drastic reduction in metastatic behaviors and significantly inhibited clonogenic survival and tumorsphere formation. Our mechanistic investigations uncovered a direct interaction between PTGFRN and the immune checkpoint molecule B7-H3. We further show that PTGFRN regulates key pro-survival and pro-metastatic signaling pathways by activating FAK/Src, a crucial kinase cascade. A central finding of our work is that PTGFRN promotes immune evasion. We demonstrate that knockdown of PTGFRN sensitizes HCC cells to natural killer (NK) cell-mediated cytotoxicity, an effect that is reversed upon restoration of PTGFRN expression. PTGFRN overexpression also inhibited NK cell-mediated cytotoxicity. Finally, analysis of human HCC tissues revealed PTGFRN expression in 74% of samples, with frequent co-expression of B7-H3, suggesting its widespread clinical relevance. These findings establish PTGFRN as a novel dual-function oncogenic driver that enhances metastatic potential and orchestrates immune escape in HCC, making it an attractive target for the development of new immunotherapeutic and anti-metastatic strategies.