Multi-Omics Approaches Identify Necroptosis‑Related Prognostic Signature and Associated Regulatory Axis in Cervical Cancer

BACKGROUND: Cervical cancer is the fourth most frequent malignancy among women globally, with approximately 604,000 new cases and 341,000 deaths per year. Necroptosis is a newly discovered mechanism of cell death involved in biological behaviors of cancer. METHODS: LASSO Cox regression analysis was conducted to construct a prognostic necroptosis-related signature. lncRNA–miRNA–mRNA regulatory axis was constructed with a ceRNA network. qRT-PCR was performed to verify our result. RESULTS: A total of 54 necroptosis-related genes were differentially expressed in cervical cancer (all p < 0.05). We also summarized genetic mutation landscape of necroptosis-related genes in cervical cancer. We then developed a necroptosis-related prognostic signature including 13 necroptosis-related genes (ATRX, AXL, DDX58, IDH1, ITPK1, MAP3K7, SLC39A7, TARDBP, TNF, TNFRSF1A, TNFRSF1B, TNFSF10, TRIM11) for cervical cancer. Cervical cancer patients with high riskscore had a poor overall survival (HR = 2.128, p = 0.00194) with an AUC of 0.725, 0.763 and 0.637 in 3-year, 5-year, and 10-year ROC curve. Consensus clustering analysis revealed that all cervical cancer cohort could be divided into three subtypes, which was correlated with different prognosis and immune infiltration (p < 0.05). A PPI network revealed TNF as the hub gene and TNF expression was correlated with immune infiltration (all p < 0.05), microsatellite instability (p < 0.012) and drug sensitivity (p < 0.05). The ceRNA network was performed and identified a lncRNA NUTM2B-AS1/miR-361-5p/TNF regulatory axis for cervical cancer. qRT-PCR result also suggested that TNF was upregulated in cervical cancer (p < 0.001) and associated with a poor overall survival (p = 0.007). Univariate and multivariate analysis demonstrated TNF expression, lymph node metastasis and clinical stage were prognosis factors of cervical cancer patients (p < 0.05). CONCLUSION: We developed a necroptosis-related prognostic signature including 13 necroptosis-related genes for cervical cancer. Moreover, we also identified a lncRNA NUTM2B-AS1/miR-361-5p/TNF regulatory axis, which may play a vital role in the progression of cervical cancer. Further studies should be conducted to verify these results.