Epigenetic Silencing of GFRA1 Promotes Cervical Cancer Metastasis via SERPINE1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1238462 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32783074_1.fastq.gz | Fastqsanger.gz | |||
| SRR32783074_2.fastq.gz | Fastqsanger.gz | |||
| SRR32783075_1.fastq.gz | Fastqsanger.gz | |||
| SRR32783075_2.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Neoadjuvant chemotherapy (NACT) followed by radical surgery for patients in FIGO stages IB2-IIB has proven to reduce tumor volume and numbers. However, NACT followed by radical surgery has not been found to improve overall survival. In this study, 35 paired pre/post-NACT cervical cancer tissues and 167 cervical cancer samples were examined by immunohistochemical analysis, SLUG expression was potentially increased in cervical cancer tissues after neoadjuvant chemotherapy, which in turn positively correlated with pelvic lymph node metastasis. The expression of SLUG following neoadjuvant chemotherapy was identified as a poor survival indicator. Functional assays, Agilent microarray hybridization and CHIP assay were performed to determine SLUG’s downstream genes and pathways. SLUG overexpression promoted metastasis in cervical cancer in both in vitro and in vivo models, whereas SLUG silencing had the opposite effect. Mechanically, SLUG is not a prerequisite for EMT activation in cervical cancer models, but contributes to the invasiveness and metastasis of cervical cancer cells by directly tethering to the recognition sequence GCCAGGTGC in the MMP3 promoter region. Our results provide mechanistic insight into the potential pro-cancer effect of neoadjuvant chemotherapy, and demonstrates that the SLUG-MMP3 axis could serve as a target for improving the efficacy of chemotherapy.
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