Integrated analysis of EREG expression, a gene associated with cervical cancer prognosis

Cervical cancer (CC) is the fourth most gynecological malignancy in the world. The identification of predictive markers can provide a basis for personalized treatment and prognostic evaluation. Our aim was to identify a new predictive marker of epiregulin (EREG) gene and explore its functional characteristics of CC and other cancer types. Differentially highly expressed genes were obtained from Gene Expression Omnibus (GEO) databases. Key genes can be verified by the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) data, and the functions of these genes were investigated through gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Survival analysis were performed to determine the key genes (EREG) related to the prognosis of CC. Then, the expression difference of EREG between tumor and normal tissue was evaluated by real-time polymerase chain reaction (PCR), western blotting, and immunohistochemistry. The relationship between EREG and prognosis of patients, immune microenvironment, immune checkpoint, immune therapy and angiogenesis was discussed in 33 tumor types. Finally, the regulatory mechanism of EREG on human umbilical vein endothelial cells (HUVECs) was also explored. The differential analysis results from multiple databases showed that EREG was significantly highly expressed in CC, which was further verified in Hela and Siha cell lines. Then, Survival analysis revealed that EREG was associated with the prognosis of CC and other tumor types, and high EREG expression was significantly associated with poor prognosis. In addition, in almost all tumor types, the expression of EREG was related to immune cells infiltration, immune checkpoint genes expression and immunotherapy. Further analysis exhibited that high EREG expression can promote the high expression of angiogenesis related genes. The experimental data demonstrated that EREG could promote the proliferative, migration, invasive and tube formation of HUVECs by interacting with receptors, such as epidermal growth factor receptor (EGFR and ERBB4). EREG may be an independent prognostic marker for predicting tumor prognosis and immunotherapy response of various cancers, and may be a potential target of tumor anti-angiogenic therapy in CC.