Expression of “Hallmarks of Cancer” Genes in Cervical Carcinoma Is Differentially Affected by GPER1 Overexpression Depending on Histologic Entity
Cervical cancer (CC) remains the fourth most common malignancy in women worldwide. Current treatments primarily consist of surgery and combined radiochemotherapy, while targeted therapies, as seen in other malignancies, remain underdeveloped. The G-protein-coupled estrogen receptor (GPER1) is implicated in various cancers and can differentially influence tumor behavior, though its precise role in CC remains unclear, with both tumor-promoting and tumor-suppressive effects reported. We previously explored the impact of stable GPER1 overexpression (OE) in CC cell lines, SiHa (cervical squamous cell carcinoma, CSCC) and HeLa (cervical adenocarcinoma, CAC), analyzing proliferation, migration, invasion, apoptosis, and stem cell properties. GPER1-OE enhanced tumorigenic properties in CSCC cells but demonstrated tumor-suppressive effects in CAC cells. To investigate the underlying mechanisms, we conducted next-generation sequencing (NGS) analyses, which supported our earlier findings. SiHa CSCC and HeLa CAC cells with stable GPER1-OE were generated. The effects of GPER1-OE on gene expression were then examined using next-generation sequencing (NGS) analyses. In CSCC cells, GPER1-OE upregulated genes involved in tumorigenic pathways, including epithelial-to-mesenchymal transition (EMT), mTOR-C1, Myc, p53, hypoxia, and angiogenesis signaling. In CAC cells, however, GPER1-OE downregulated these pathways, along with additional pathways such as KRAS, Hedgehog, TNFα ( The results highlight the divergent roles of GPER1-OE in CC cells, promoting oncogenesis in CSCC while exerting tumor-suppressive effects in CAC by modulating oncogenic signaling pathways.