WT1-AS acts as a tumor suppressor in cervical cancer via OSR2-mediated transcriptional activation.

BACKGROUNDCervical cancer (CESC) remains a major global health burden, and its molecular mechanisms are not fully understood. Long non-coding RNAs (lncRNAs) have emerged as critical regulators in tumor biology. Among them, Wilms tumor 1 antisense RNA (WT1-AS) has been implicated in several cancers, but its role in CESC is largely unknown. Therefore, this study aimed to investigate the expression pattern, prognostic significance, biological function, and upstream transcriptional regulation of WT1-AS in CESC.

METHODSWe performed a comprehensive analysis integrating The Cancer Genome Atlas (TCGA) pan-cancer and CESC datasets to examine the expression profile and prognostic relevance of WT1-AS. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and single-cell RNA sequencing analyses were conducted to explore its biological functions. Functional assays, including Western blotting, flow cytometry, and xenograft mouse models, were performed to validate the effects of WT1-AS on apoptosis and tumor growth. Upstream transcriptional regulation was investigated using transcription factor prediction, co-expression analysis, and luciferase reporter assays.

RESULTSWT1-AS was significantly dysregulated across multiple cancers and correlated with poor prognosis in several tumor types. In CESC, WT1-AS was primarily expressed in malignant epithelial cells and fibroblasts and was functionally enriched in apoptosis- and extracellular matrix-related pathways. Overexpression of WT1-AS promoted apoptosis, as evidenced by increased cleaved-caspase3 and cleaved-PARP expression, and suppressed tumor growth in vivo. Mechanistically, odd-skipped related transcription factor 2 (OSR2) was identified as a direct transcriptional regulator of WT1-AS. Overexpression of OSR2 enhanced apoptosis, and co-overexpression with WT1-AS further amplified pro-apoptotic effects.

CONCLUSIONSOur findings reveal that WT1-AS functions as a tumor suppressor in CESC by promoting apoptosis and identify OSR2 as a novel upstream regulator. The WT1-AS/OSR2 axis may have biological and potential prognostic relevance in CESC, although its clinical applicability requires further validation.