Oncosuppressive Role of RUNX3 in Human Astrocytomas
Giedrius Steponaitis1, Arunas Kazlauskas1, Paulina Vaitkienė1
1Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu Str. 4, 50161 Kaunas, Lithuania.
Background:
Gliomas are the most common and aggressive among primary malignant brain tumours with significant inter- and intratumour heterogeneity in histology, molecular profile, and patient outcome. However, molecular targets that could provide reliable diagnostic and prognostic information on this type of cancer are currently unknown. Recent studies show that certain phenotypes of gliomas such as malignancy, resistance to therapy, and relapses are associated with the epigenetic alterations of tumour-specific genes. Runt-related transcription factor 3 (RUNX3) is feasible tumour suppressor gene since its inactivation was shown to be related to carcinogenesis.
Aim:
The aim of the study was to elucidate RUNX3 changes in different regulation levels of molecular biology starting from epigenetics to function in particular cases of astrocytic origin tumours of different grade evaluating significance of molecular changes of RUNX3 for patient clinical characteristics as well as evaluate RUNX3 reexpression effect to GBM cells.
Methods:
The methylation status and protein expression levels of RUNX3 were measured by methylation-specific PCR and Western blot in 136 and 72 different malignancy grade glioma tissues, respectively. Lipotransfection and MTT were applied for proliferation assessment in U87-MG cells.
Results:
We found that RUNX3 was highly methylated and downregulated in GBM. RUNX3 promoter methylation was detected in 69.4% of GBM (n=49) as compared to 0 to 17.2% in I-III grade astrocytomas (n=87). Weighty lower RUNX3 protein level was observed in GMB specimens compared to grade II-III astrocytomas. Correlation test revealed a weak but significant link among Runx3 methylation and protein level. Kaplan-Meier analysis showed that increased RUNX3 methylation and low protein level were both associated with shorter patient survival (p<0.05). Reexpression of RUNX3 in U87-MG cells significantly reduced glioma cell viability compared to control transfection.
Conclusions:
The results demonstrate that RUNX3 gene methylation and protein expression downregulation are glioma malignancy dependent and contribute to tumour progression.
Insights
Runt-related transcription factor 3 (RUNX3) gene methylation and protein downregulation are linked to glioma progression and poorer patient survival. Restoring RUNX3 expression reduced glioma cell viability, suggesting its therapeutic potential.
Area of Science:
- Molecular oncology
- Epigenetics
- Cancer biology
Background:
- Gliomas are aggressive brain tumors with significant heterogeneity and unknown molecular targets.
- Epigenetic alterations in tumor suppressor genes are linked to glioma malignancy, therapy resistance, and relapse.
- Runt-related transcription factor 3 (RUNX3) is a potential tumor suppressor gene implicated in carcinogenesis.
Purpose of the Study:
- To investigate RUNX3 alterations at epigenetic and functional levels in astrocytic gliomas of varying grades.
- To evaluate the significance of RUNX3 molecular changes for patient clinical characteristics.
- To assess the effect of RUNX3 reexpression on glioblastoma (GBM) cells.
Main Methods:
- Assessed RUNX3 methylation status and protein expression in 136 and 72 glioma tissues, respectively, using methylation-specific PCR and Western blot.
- Utilized lipotransfection and MTT assays to evaluate proliferation in U87-MG glioblastoma cells.
Main Results:
- RUNX3 was highly methylated and downregulated in glioblastoma (GBM) compared to lower-grade astrocytomas.
- Increased RUNX3 promoter methylation and low protein levels correlated with shorter patient survival.
- Reexpression of RUNX3 significantly reduced glioma cell viability in vitro.
Conclusions:
- RUNX3 gene methylation and protein downregulation are dependent on glioma malignancy and contribute to tumor progression.
- RUNX3 alterations serve as potential diagnostic and prognostic markers for gliomas.
- RUNX3 reexpression demonstrates therapeutic potential for glioblastoma treatment.
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