Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors, with an extremely poor prognosis. Telomeres lenght is associated with tumor progression in several type of human cancers and telomere elongation is a common molecular feature of advanced malignancies. Among the telomeric shelterin proteins PTOP is required for telomeric protein complex assembly, telomerase recruitment and activity, and telomere length regulation through a PTOP-telomerase interaction. Aim of our study is to investigate the expression of PTOP in different grades of human glioma and its correlation with the pathological grade of gliomas, grades of malignancy, proliferative activity and apoptosis. Fifteen Low Grade Astrocytomas (LGA), 18 Anaplastic Astrocytomas (AA) and 26 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. More, we examined the expression profile of PTOP in human glioma cell line and U87MG and in radioresistant clone U87R subjected to therapeutic doses of IR. The expression levels of PTOP and h-TERT were determined by real time PCR and/or western blot. Results obtained showed that PTOP expression in glioma tissues was tightly correlated with clinical grade (p<0.01). No correlation was found between PTOP expression and other clinicopathologic parameters. The levels of PTOP were positively correlated with the expression of hTERT and TERF1. In irradiated cells, PTOP expression was increased in a IR-dose dependent manner, particularly when a dose of ≥6 Gy was administered. An higher expression of PTOP was observed in the radioresistant clone than the parental cells. Otherwise, silencing of PTOP results in a radiation sensitivity enhancement and decrease of telomerase activity. Our findings indicate that PTOP might play key role in the progression and radioresistance of gliomas regulating telomerase activity and likely through regulation of cell cycle and apoptosis. In conclusion results obtained suggest that PTOP might be involved in cancer radioresistance and might represents a potential molecular biomarker and a therapeutic target for the treatment of glioblastoma tumors.
PTOP expression correlates with telomerase activity and grades of malignancy in human gliomas
Francesca PolitoMethodology
;Stefano PergolizziMembro del Collaboration Group
;Rosaria V. AbbrittiMembro del Collaboration Group
;Domenico La TorreMembro del Collaboration Group
;Antonino GermanòResources
;M’hammed Aguennouz.Writing – Original Draft Preparation
2016-01-01
Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors, with an extremely poor prognosis. Telomeres lenght is associated with tumor progression in several type of human cancers and telomere elongation is a common molecular feature of advanced malignancies. Among the telomeric shelterin proteins PTOP is required for telomeric protein complex assembly, telomerase recruitment and activity, and telomere length regulation through a PTOP-telomerase interaction. Aim of our study is to investigate the expression of PTOP in different grades of human glioma and its correlation with the pathological grade of gliomas, grades of malignancy, proliferative activity and apoptosis. Fifteen Low Grade Astrocytomas (LGA), 18 Anaplastic Astrocytomas (AA) and 26 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. More, we examined the expression profile of PTOP in human glioma cell line and U87MG and in radioresistant clone U87R subjected to therapeutic doses of IR. The expression levels of PTOP and h-TERT were determined by real time PCR and/or western blot. Results obtained showed that PTOP expression in glioma tissues was tightly correlated with clinical grade (p<0.01). No correlation was found between PTOP expression and other clinicopathologic parameters. The levels of PTOP were positively correlated with the expression of hTERT and TERF1. In irradiated cells, PTOP expression was increased in a IR-dose dependent manner, particularly when a dose of ≥6 Gy was administered. An higher expression of PTOP was observed in the radioresistant clone than the parental cells. Otherwise, silencing of PTOP results in a radiation sensitivity enhancement and decrease of telomerase activity. Our findings indicate that PTOP might play key role in the progression and radioresistance of gliomas regulating telomerase activity and likely through regulation of cell cycle and apoptosis. In conclusion results obtained suggest that PTOP might be involved in cancer radioresistance and might represents a potential molecular biomarker and a therapeutic target for the treatment of glioblastoma tumors.Pubblicazioni consigliate
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