Epigenetic Silencing of GFRA1 Promotes Cervical Cancer Metastasis via SERPINE1

Cervical cancer (CC) is the fourth most common malignancy among women worldwide. The abnormal methylation of oncogenes/tumor suppressor genes can lead to the occurrence and progression of cervical cancer. Here, we identified GFRA1 as an abnormally methylated gene in CC, with its expression levels inversely correlated with promoter methylation. GFRA1 promoter hypermethylation was consistently observed in cervical cancer cell lines and tumor tissues, accompanied by significantly reduced expression compared to normal counterparts. Functional assays demonstrated that GFRA1 overexpression suppressed cervical cancer cell migration in vitro and inhibited lung metastasis formation in vivo. Integrated RNA-Seq and network analyses revealed SERPINE1 as the key downstream effector, whose overexpression enhanced the migratory capacity of cervical cancer cells both in vitro and in vivo. In summary, this study reveals that GFRA1 promoter hypermethylation silences its expression, promoting CC metastasis via SERPINE1. Therefore, our findings contribute to the understanding of the potential role of GFRA1 methylation in cervical cancer and may serve as a potential diagnostic and therapeutic target for cervical cancer.