DNMT1-mediated silencing of SFRP1 promotes endometrial carcinogenesis through the Wnt/β-catenin pathway.

BACKGROUND: Endometrial cancer (EC) incidence is rising globally. Secreted Frizzled-Related Protein 1 (SFRP1) is often silenced in cancers, but its functional role in EC remains unclear. METHODS: Expression and clinical relevance of SFRP1 in EC were analyzed using GEPIA database and validated in clinical specimens via RT-qPCR. The functional impact of SFRP1 was assessed in EC cells through gain-of-function (overexpression plasmid) and loss-of-function (silencing siRNA) experiments. Key cellular phenotypes,including viability (CCK-8), proliferation (Ki-67 staining, colony formation), migration (wound healing), invasion (Transwell), and apoptosis (flow cytometry), were evaluated. In vivo tumor growth and metastasis were examined in BALB/c nude mice using subcutaneous xenograft and experimental lung colonization models. The involvement of Wnt/β-catenin pathway was analyzed by western blot. The epigenetic regulation of SFRP1 by DNA methyltransferase 1 (DNMT1) was investigated through methylation-specific PCR (MSP) and chromatin immunoprecipitation (ChIP)-qPCR. RESULTS: SFRP1 downregulation correlated with advanced grade and poor prognosis. Functionally, SFRP1 consistently inhibited proliferation, migration, invasion, and tumor growth while promoting apoptosis in both in vitro and in vivo models. Mechanistically, SFRP1 exerted anti-tumor effects by negatively regulating Wnt/β-catenin signaling, and its transcriptional repression was caused by DNMT1-mediated promoter hypermethylation. CONCLUSION: SFRP1 acts as a tumor suppressor in EC by inhibiting Wnt/β-catenin, and its downregulation is driven by DNMT1-mediated promoter methylation.