Abstract
Enhanced expression of TERT in gliomas is a result of two hotspot mutations, C228T and C250T, at the promoter region. GA-binding proteins selectively bind at these positions, respectively, causing an activation of the promoter and overexpression of TERT. GABP is a multimeric protein consisting of GABPA and GABPB with its isoforms GABPB1, GABPB1-L, GABPB1-S, GABPB2.In this study, we investigated the mRNA expression and association between TERT and GABPA/B isoforms in tumor samples of different glioma grades. The expression was determined by quantitative real-time PCR and the results were statistically analyzed.We present that TERT is mainly expressed in primary glioblastomas. All GA-binding proteins progress through the glioma grades and have the highest expression levels in secondary glioblastomas. In secondary glioblastomas after chemotherapy, GABPB1 and GABPB1-L are expressed on a lower level than without treatment. In high grades, TERT and GABPA, GAPB1, GABPB1-L, GABPB1-S are upregulated compared to low grades. Between primary and secondary glioblastomas with and without chemotherapy, TERT is elevated in the former while GABPB1 is increased in the secondary glioblastomas. GABPA and GABPB1, GABPB1-L and GABPB1-S positive correlate in primary glioblastomas.The present study confirms the upregulation of TERT in primary glioblastomas while all GABP proteins rise with the malignancy of the gliomas. Further investigations must be made to elucidate the relation between TERT and all GABP proteins as it may play a key role in the gliomagenesis.
Highlights
Gliomas are the most common primary tumors of the central nervous system (CNS)
Regarding the quantitative real-time PCR results and statistical analysis of our glioma cohorts we show that Telomerase reverse transcriptase (TERT) mRNA is mostly expressed in primary glioblastoma multiforme (GBM) and in primary GBM which had been treated with chemotherapy compared to the control group with p = 0.007, respectively, without any difference between the two prim
Subgrouping the different glioma groups in low and high grade gliomas (LGG and HGGs) consisting of grade III and secondary glioblastomas without chemotherapy, TERT and GABPA, -B1, -B1-L and -B1-S were overexpressed in the HGGs (TERT: mean = 0.023, 95% CI = 0.01–0.03, p = 0.023, GABPA: mean = 0.196, 95% CI = 0.15–0.23, p = 0.0005, GABPB1: mean = 0.524, 95% CI = 0.44–0.6, p = 0.016, GABPB1-L: mean = 0.448, 95% CI = 0.34–0.55, p < 0.0001 and GABPB1-S: mean = 0.538, 95% CI = 0.37–0.69, p < 0.0001) (Figure 2)
Summary
Gliomas are the most common primary tumors of the central nervous system (CNS). They comprise the diffuse astrocytomas and oligodendrogliomas World Health Organization (WHO) grade II, the anaplastic astrocytomas and oligondendrogliomas WHO grade III and the most frequent one, the glioblastoma multiforme (GBM) WHO grade IV [1]. 83% of the primary glioblastomas harbor those hotspot mutations with a different distribution between C228T and C250T (73% vs 27%) while in lower glioma grades they seem to be rare [13, 14] In this way, the mutant promoter status correlates with the elevated mRNA levels of TERT and with the increased telomerase activation [15]. The mutant promoter status correlates with the elevated mRNA levels of TERT and with the increased telomerase activation [15] Both non-coding mutations at the promoter generate a purine-rich GGAAG binding site for the transcription factor GA-binding protein (GABP) of the E-twenty-six (Ets) family [16]. In this study we investigated the mRNA expression level of TERT and all GABPA/B isoforms and their correlation and interplay in the grade II, grade III gliomas as well as in the primary and secondary glioblastomas to understand their role in the gliomagenesis
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