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Updated: Jan 21, 2026
Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Ral GTPase Activation by Downregulation of RalGAP Enhances Oral Squamous Cell Carcinoma Progression
P Gao1,2,3, S Liu4, R Yoshida5
11 State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of General and Emergency Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Abstract:
Ral small GTPases, consisting of RalA and RalB, are members of the Ras family. Their activity is upregulated by RalGEFs. Since several RalGEFs are downstream effectors of Ras, Ral is activated by the oncogenic mutant Ras. Ral is negatively regulated by RalGAP complexes that consist of a catalytic α1 or α2 subunit and its common partner β subunit and similarly regulate the activity of RalA as well as RalB in vitro. Ral plays an important role in the formation and progression of pancreatic and lung cancers. However, the involvement of Ral in oral squamous cell carcinoma (OSCC) is unclear. In this study, we investigated OSCC by focusing on Ral. OSCC cell lines with high Ral activation exhibited higher motility. We showed that knockdown of RalGAPβ increased the activation level of RalA and promoted the migration and invasion of HSC-2 OSCC cells in vitro. In contrast, overexpression of wild-type RalGAPα2 in TSU OSCC cells attenuated the activation level of RalA and inhibited cell migration and invasion. Real-time quantitative polymerase chain reaction analysis of samples from patients with OSCC showed that RalGAPα2 was downregulated in oral cancer tissues as compared with normal epithelia. Among patients with OSCC, those with a lower expression of RalGAPα2 showed a worse overall survival rate. A comparison of DNA methylation and histone modifications of the RalGAPα2 gene in OSCC cell lines suggested that crosstalk among DNA methylation, histone H4Ac, and H3K27me2 was involved in the downregulation of RalGAPα2. Thus, activation of Ral GTPase by downregulation of RalGAP expression via a potential epigenetic mechanism may enhance OSCC progression.
Insights
Ral GTPases are implicated in oral cancer progression. Downregulation of RalGAPα2, potentially via epigenetic changes, increases Ral GTPase activity, promoting oral squamous cell carcinoma (OSCC) cell migration and invasion.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Ral small GTPases (RalA and RalB) are Ras family members activated by RalGEFs, which are downstream of Ras.
- Ral GTPase activity is negatively regulated by RalGAP complexes.
- Ral is known to be involved in pancreatic and lung cancers, but its role in oral squamous cell carcinoma (OSCC) is not well understood.
Purpose of the Study:
- To investigate the role of Ral GTPase and its regulator RalGAP in oral squamous cell carcinoma (OSCC).
- To explore the potential epigenetic mechanisms underlying RalGAP downregulation in OSCC.
Main Methods:
- Investigated Ral activation in OSCC cell lines.
- Utilized gene knockdown (RalGAPβ) and overexpression (RalGAPα2) in OSCC cell lines to assess effects on cell motility, migration, and invasion.
- Performed real-time quantitative polymerase chain reaction (RT-qPCR) on patient samples to analyze RalGAPα2 expression.
- Examined DNA methylation and histone modifications of the RalGAPα2 gene in OSCC cell lines.
Main Results:
- Higher Ral activation correlated with increased motility in OSCC cell lines.
- Knockdown of RalGAPβ enhanced RalA activation and promoted migration/invasion in HSC-2 cells.
- Overexpression of RalGAPα2 attenuated RalA activation and inhibited migration/invasion in TSU cells.
- RalGAPα2 expression was significantly downregulated in oral cancer tissues compared to normal epithelia.
- Lower RalGAPα2 expression in OSCC patients correlated with worse overall survival.
- Epigenetic modifications, including DNA methylation and histone H4Ac/H3K27me2 crosstalk, were implicated in RalGAPα2 downregulation.
Conclusions:
- Ral GTPase activation, driven by RalGAP downregulation through epigenetic mechanisms, contributes to OSCC progression.
- RalGAPα2 downregulation is a potential biomarker for poor prognosis in OSCC.
- Targeting the Ral GTPase pathway or addressing epigenetic dysregulation may offer therapeutic strategies for OSCC.
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