Abstract
BackgroundGlioma is a heterogeneous, invasive primary brain tumor with a wide range of patient survival and a lack of reliable prognostic biomarkers. Human telomerase reverse transcriptase (hTERT) has been reported in the presence of multiple transcripts in various tumor systems. The biological function and precise regulatory mechanisms of hTERT transcripts remain uncertain.MethodsAlternative splicing of hTERT and telomerase activity were examined in 96 glioma specimens, including 38 glioblastomas (GBMs), 23 oligodendrogliomas (ODMs), and 35 oligoastrocytomas (OAMs). The correlation between telomerase activity or hTERT transcripts and patient clinical characteristics was investigated. We examined the regulation of alternative splicing of hTERT and telomerase activity by G-quadruplex stabilizer CX-5461 in GBM cells. The biological effects of CX-5461 on GBM cell lines, including inhibition of cell proliferation, effects on cell cycle/apoptosis, and telomere DNA damage were further explored.ResultsThe β splicing was verified in human gliomas and hTERT+β was significantly correlated with higher telomerase activity, higher KPS, larger tumor size, and higher tumor grades. Meanwhile, glioma patients lacking hTERT+β expression or telomerase activity showed a significant survival benefit. Notably, CX-5461 altered hTERT splicing patterns, leading to an increase of hTERT-β transcript and a decrease of hTERT+β transcript expression, which inhibits telomerase activity. In addition, CX-5461 had cytotoxic effects on GBM cells and caused telomere DNA damage response, induced G2/M arrest and apoptosis.ConclusionsThe hTERT+β is verified to be correlated with clinical parameters in gliomas, and could serve as a prognostic marker or possibly therapeutic target for gliomas. CX-5461 can regulate the splicing pattern of hTERT, inhibit telomerase activity, and kill GBM cells.
Highlights
Glioma is a heterogeneous, invasive primary brain tumor with a wide range of patient survival and a lack of reliable prognostic biomarkers
We examined the regulation of alternative splicing of Human telomerase reverse transcriptase (hTERT) and telomerase activity by G-quadruplex stabilizer CX-5461 in GBM cells
Results hTERT alternative splice variant patterns in human gliomas and cell lines We investigated hTERT transcript patterns by RT-PCR, and found that hTERT-All expressed in all human glioma tissues and cell lines (Fig. 1b-e)
Summary
Invasive primary brain tumor with a wide range of patient survival and a lack of reliable prognostic biomarkers. Human telomerase reverse transcriptase (hTERT) has been reported in the presence of multiple transcripts in various tumor systems. Li et al Journal of Experimental & Clinical Cancer Research (2018) 37:78 studies have shown the presence of different transcripts of hTERT, including three deletions and four insertions, which may affect telomerase activity and biological functions [10,11,12]. Four insertions and the β and γ deletion result in nonfunctional proteins whereas the α deletion is a dominant negative inhibitor of telomerase activity [13, 14]. The most widely studied variants involve splicing at two main sites: the α splice site in exon 6, which produces a 36-bp in frame deletion within the conserved reverse transcript motif A; and the β splice site in exon 7 and exon 8, which results in a 182-bp deletion and nonsense mutation that truncates the protein [15,16,17,18] (Fig. 1a). Alternative splicing of hTERT mRNA has been shown to contribute to the regulation of telomerase activity and might be used as an additional prognostic marker in certain types of malignancies
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