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Alternative splicing of human telomerase reverse transcriptase in gliomas and its modulation mediated by CX-5461
Li, Guihong (Zhengzhou, 450000 China)
Shen, Jing (Department of Cardiology, Shengze Hospital of Jiangsu Province, Suzhou, 215200 China)
Cao, Junguo (Changchun, 130021 China)
Zhou, Guangtong (Zhengzhou, 450000 China)
Lei, Ting (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sun, Yuxue (Changchun, 130021 China)
Gao, Haijun (Changchun, 130021 China)
Ding, Yaonan (Changchun, 130021 China)
Xu, Weidong (Changchun, 130021 China)
Zhan, Zhixin (Changchun, 130021 China)
Chen, Yong (Changchun, 130021 China)
Huang, Haiyan (Changchun, 130021 China)
Universitat Autònoma de Barcelona

Data: 2018
Resum: Glioma 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. Alternative 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. The 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. The 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.
Nota: Altres ajuts: This study was partially supported by the Young Scientists Fund of the National Natural Science Foundation of China (Nos. 21401072), National Science Foundation of China (Nos.81672505) and the S&T Development Planning Program of Jilin Province (Nos. 20150312005ZG).
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: Glioma ; Human telomerase reverse transcriptase (hTERT) ; Alternative splicing ; CX-5461 ; G-quadruplex
Publicat a: Journal of Experimental & Clinical Cancer Research : CR, Vol. 37 (april 2018) , ISSN 1756-9966

DOI: 10.1186/s13046-018-0749-8
PMID: 29631594

13 p, 2.4 MB

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