EGF Family-Based Prognostic Model Reveals AREG as a Key Regulator in Cervical Cancer Progression

This study investigates the prognostic value of Epidermal Growth Factor (EGF) family genes in Cervical Cancer (CC) and experimentally validates the role of AREG in the progression of CC.

Transcriptome and clinical data of CC were obtained from the TCGA database. We constructed a prognostic model using LASSO Cox regression analysis based on candidate EGF family genes. Multiple bioinformatics approaches were employed to analyze functional pathways and immune characteristics. The biological function of Amphiregulin (AREG) was validated through in vitro experiments, including colony formation, CCK8 proliferation assay, wound healing assay, transwell assay, macrophage polarization analysis using the co-culture system, and in vivo subcutaneous tumor formation in nude mice. Combination therapy with anti-AREG and anti-PD-L1 antibodies was evaluated in a murine C57BL/6 model.

We identified 116 EGF family-related genes associated with CC progression and established a prognostic model. High-risk and low-risk groups showed distinct functional enrichment patterns and immune characteristics. AREG emerged as a key prognostic factor, with significantly elevated expression in CC cells. Knockdown of AREG suppressed CC cell proliferation, migration, and invasion, potentially through modulating Epithelial-Mesenchymal Transition (EMT). AREG promoted M2 macrophage polarization, fostering an immunosuppressive tumor microenvironment. Anti-AREG antibody treatment demonstrated antitumor effects in vitro and in vivo, synergizing with anti- PD-L1 therapy to significantly inhibit tumor growth and reverse EMT.

Our findings establish the first EGF family-based prognostic model for CC and reveal AREG's dual role in promoting EMT and reshaping the immune microenvironment. The observed synergy between AREG inhibition and PD-L1 blockade provides mechanistic insights for overcoming immunotherapy resistance. Limitations include retrospective data analysis and a lack of multi-omics validation.

Our study establishes a robust EGF family gene-based prognostic model for CC patients and identifies AREG as a promising therapeutic target. These findings provide new insights for CC prognosis assessment and treatment strategies.