Abstract
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.
Highlights
Glial brain tumours originating from glial cells are intracranial solid neoplasms
In present analysis we demonstrated that RUNX3 is starting to be deregulated from very onset of gliomagenesis at both epigenetic and functional levels and these changes are tightly associated with patient age and survival as well as tumour pathological grade
Mueller with colleagues were first to show that RUNX3 is hypermethylated in glioblastoma cell lines and primary glioma tumour tissue cells compared to normal human brain tissue
Summary
Glial brain tumours originating from glial cells are intracranial solid neoplasms. According to classification system of the World Health Organisation (WHO) based on histological evaluation, brain tumour grade is determined by necrotic cells in the centre of the tumour, increased mitotic activity, the presence of nuclear pleomorphism, and angiogenesis. Brain tumour malignancy is associated with tumour heterogeneity, recurrence, patient survival, and therapy response [1]. 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. 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. 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. The results demonstrate that RUNX gene methylation and protein expression downregulation are glioma malignancy dependent and contribute to tumour progression
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