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Epigenetic Silencing of GFRA1 Promotes Cervical Cancer Metastasis via SERPINE1

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292433 | GEO | 2025/05/31

REPOSITORIES: GEO

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Project description:A large-scale characterization of the methylation states of candidate CpG islands (CGIs) throughout the gastric cancer methylome has not previously been conducted. Genome-wide DNA methylation profiles were compared between 4 metastatic and 4 non-metastatic gastric carcinomas (GCs) and their surgical margins (SMs). The GC genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared to SMs. Differential methylation was observed in CGIs near transcription start sites of 546 genes between GCs and SMs, and 601 genes between metastatic and non-metastatic GCs. From the list of differentially methylated CGIs, 68 candidate genes and 10 known tumor-related genes were selected for further characterization based on their known molecular function using DHPLC. Significant differential methylation was validated in the CGIs of 15 genes between GCs and SMs (Ps<0.05) and confirmed using bisulfite-sequencing. These genes include BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Hypomethylation of CGIs correlated with up-regulation of GFRA1 expression in GCs, while hypermethylation of other genes inactivated their transcription. Most importantly, prevalence of GFRA1, SRF, and ZNF382 methylation alterations were inversely and coordinately associated with GC metastasis and the patients’ overall survival throughout discovery and testing cohorts in China as well as independent validation cohorts in Japan and Korea. In conclusion, methylation changes in the CGIs of 15 genes correlated strongly with GC development. GFRA1 hypomethylation and SRF and ZNF382 hypermethylation are potential synergistic biomarkers for the prediction of GC metastasis. To identify differential methylation of CGIs related to GC development and metastasis, genome-wide DNA methylation changes in 8 pairs of GC and SM samples were analysed using the MCAM assay with a 99K custom-designed Agilent oligonucleotide microarray composed of 99,027 probes targeting 6,177 unique protein-coding genes containing at least two methylation-sensitive/insensitive SmaI/ XmaI restriction sites (CCC|GGG/ C|CmCGGG) as described in Shen et al, PLoS Genet 3, 2023-2036 (2007).

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Epigenetic Silencing of GFRA1 Promotes Cervical Cancer Metastasis via SERPINE1

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