Oncotarget: TERT and its binding protein: overexpression of GABPA/B in gliomas

image: Correlation of TERT vs. GABPB1/-S and GABPB1, GABPB1-L, GABPB1-S and GABPB2 vs. GABPBA mRNA expression in gliomas. Black line indicates trend-line and Pearson's rank order correlation was used to generate Pearson rho and p-values for each correlation. (A) No correlation between TERT and moreover, in primary glioblastomas (r = 0.18). (B) negative linear correlation between TERT and in addition, in grade III gliomas (r = -0.65, p = 0.003). (C-E) GABPA correlates positive with GABPB1, GABPB1-L and GABPB1-S in primary glioblastomas with p = 0.035, 0.0008 and 0.045, respectively. (F) GABPA and GABPB2 have the tendency to slightly positive correlate in primary glioblastomas, without any statistical significance, n.s.: no significance.

Correspondence to - Marco Timmer - marco.timmer@uk-koeln.de

Oncotarget published "TERT and its binding protein: overexpression of GABPA/B in high grade gliomas" which reported that 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.

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 positively correlate in primary glioblastomas.

This Oncotarget study confirms the upregulation of TERT in primary glioblastomas while all GABP proteins rise with the malignancy of the gliomas.

This Oncotarget study confirms the upregulation of TERT in primary glioblastomas while all GABP proteins rise with the malignancy of the gliomas.

Dr. Marco Timmer from The University of Cologne said, "Gliomas are the most common primary tumors of the central nervous system (CNS)"

They comprise the diffuse astrocytomas and oligodendrogliomas World Health Organization grade II, the anaplastic astrocytomas and oligondendrogliomas WHO grade III and also the most frequent one, the glioblastoma multiforme WHO grade IV.

These two point mutations occur frequently in tumor cells that do not need a continual regeneration such as melanomas and gliomas.

Among the gliomas, 83% of the primary glioblastomas harbor those hotspot mutations with a different distribution between C228T and C250T while in lower glioma grades they seem to be rare.

Recent studies showed that the GABP tetramer forming isoforms, especially GABPB1-L, activate the mutant TERT promoter and a disruption of B1L generates telomeric loss in glioblastoma cell lines introducing the importance of GABPA/B isoforms in the mutated TERT promoter dependent gliomas.

Consequently, in this study the authors 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.

The Timmer Research Team concluded in their Oncotarget Research Output that the two somatic mutations in the promoter region of TERT create a de novo binding motif for GABP .

The proof, that GABP is recruited to the hotspot mutations of the promoter, thus reactivating and inducing TERT expression in glioblastoma cell lines, gave a significant role to GABP as an transcription regulator in a TERT dependent manner and provides evidence of specific cancer interaction in the promoter core which may lead to limitless replication.

Secondary GBMs seem to have more than 80% of IDH1 mutations indicating the progression from diffuse gliomas and primary GBMs harbor fewer than 5% of IDH1 missense mutations and are identified as de novo tumors.

This research group is the first to present an upregulation of all GABP components in the different glioma grades and GABPA, -B1, -B1-L, -B1-S are gradually expressed during malignancy progression from lower to higher grade while the most expression is observed in the sec.

The authors proved that the B1L isoform is the main regulator of TERT expression in promoter mutated glioblastomas and there is a positive association between TERT and B1L mRNA expression, unlike our correlation results.

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