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Expression of "Hallmarks of Cancer" Genes in Cervical Carcinoma Is Differentially Affected by GPER1 Overexpression
Lena Hambach1, Julia Gallwas1, Carsten Gründker2
1University Medical Center Göttingen, Department of Gynecology and Obstetrics, Göttingen, Germany.
Background/Aim:
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.
Materials And Methods:
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.
Results:
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 (via NFκB), and Wnt/Beta-Catenin signaling.
Conclusion:
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.
Insights
The G-protein-coupled estrogen receptor (GPER1) has opposing roles in cervical cancer (CC) subtypes. Overexpression promotes growth in squamous cell carcinoma but suppresses it in adenocarcinoma by altering key signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cervical cancer (CC) treatments lack targeted therapies.
- The G-protein-coupled estrogen receptor (GPER1) has an unclear role in CC, with conflicting reports.
- Previous studies showed GPER1 overexpression (OE) promoted tumorigenesis in cervical squamous cell carcinoma (CSCC) but suppressed it in cervical adenocarcinoma (CAC).
Purpose of the Study:
- To investigate the molecular mechanisms behind the divergent effects of GPER1 overexpression in different cervical cancer subtypes.
- To analyze gene expression changes induced by GPER1 OE in CSCC and CAC cell lines using next-generation sequencing (NGS).
Main Methods:
- Generated stable GPER1-overexpressing (OE) SiHa (CSCC) and HeLa (CAC) cell lines.
- Utilized next-generation sequencing (NGS) to analyze global gene expression profiles in response to GPER1 OE.
Main Results:
- In CSCC cells, GPER1 OE upregulated genes in pathways promoting tumorigenesis, including epithelial-to-mesenchymal transition (EMT), mTOR-C1, Myc, p53, hypoxia, and angiogenesis.
- In CAC cells, GPER1 OE downregulated these pathways, plus KRAS, Hedgehog, TNFα, and Wnt/Beta-Catenin signaling.
Conclusions:
- GPER1 exhibits dichotomous functions in cervical cancer, promoting oncogenesis in CSCC and tumor suppression in CAC.
- These opposing effects are mediated by the modulation of distinct oncogenic signaling pathways.
- Understanding GPER1's differential roles could inform targeted therapeutic strategies for cervical cancer.
