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Brodie, S.; Lee, H.K.; Jiang, W.; Cazacu, S.; Xiang, C.; Poisson, L.M.; Datta, I.; Kalkanis, S.; Ginsberg, D.; Brodie, C. |
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Title |
The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells |
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Journal Article |
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Year |
2017 |
Publication |
Oncotarget |
Abbreviated Journal |
Oncotarget |
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Volume |
8 |
Issue |
19 |
Pages |
31785-31801 |
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Keywords |
Talnec2; glioblastoma; glioma stem cells; long non-cording RNAs; mesenchymal transformation |
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Abstract |
Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM. |
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Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA |
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1949-2553 |
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PMID:28423669 |
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ref @ user @ |
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96594 |
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Author |
Sullivan, K.E.; Rojas, K.; Cerione, R.A.; Nakano, I.; Wilson, K.F. |
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Title |
The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells |
Type |
Journal Article |
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Year |
2017 |
Publication |
Oncotarget |
Abbreviated Journal |
Oncotarget |
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Volume |
8 |
Issue |
14 |
Pages |
22325-22343 |
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Keywords |
Aldehyde Oxidoreductases/genetics/*metabolism; Biomarkers, Tumor/metabolism; Brain Neoplasms/genetics/*metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine/analogs & derivatives/pharmacology; GTP-Binding Proteins/genetics/*metabolism; Gene Expression Regulation, Neoplastic; Glioma/genetics/*metabolism; Humans; Mesenchymal Stromal Cells/*physiology; Neoplastic Stem Cells/*physiology; RNA, Small Interfering/genetics; Stem Cells/*physiology; Transglutaminases/genetics/*metabolism; Tretinoin/metabolism; Up-Regulation; aldehyde dehydrogenase; cancer stem cells; glioblastoma; retinoic acid; tissue transglutaminase |
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Abstract |
Tissue transglutaminase (tTG), a dual-function enzyme with GTP-binding and acyltransferase activities, has been implicated in the survival and chemotherapy resistance of aggressive cancer cells and cancer stem cells, including glioma stem cells (GSCs). Using a model system comprising two distinct subtypes of GSCs referred to as proneural (PN) and mesenchymal (MES), we find that the phenotypically aggressive and radiation therapy-resistant MES GSCs exclusively express tTG relative to PN GSCs. As such, the self-renewal, proliferation, and survival of these cells was sensitive to treatment with tTG inhibitors, with a benefit being observed when combined with the standard of care for high grade gliomas (i.e. radiation or temozolomide). Efforts to understand the molecular drivers of tTG expression in MES GSCs revealed an unexpected link between tTG and a common marker for stem cells and cancer stem cells, Aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3, as well as other members of the ALDH1 subfamily, can function in cells as a retinaldehyde dehydrogenase to generate retinoic acid (RA) from retinal. We show that the enzymatic activity of ALDH1A3 and its product, RA, are necessary for the observed expression of tTG in MES GSCs. Additionally, the ectopic expression of ALDH1A3 in PN GSCs is sufficient to induce the expression of tTG in these cells, further demonstrating a causal link between ALDH1A3 and tTG. Together, these findings ascribe a novel function for ALDH1A3 in an aggressive GSC phenotype via the up-regulation of tTG, and suggest the potential for a similar role by ALDH1 family members across cancer types. |
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Department of Molecular Medicine, Cornell University, Ithaca, NY, USA |
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1949-2553 |
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PMID:28423611 |
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ref @ user @ |
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96595 |
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Glaser, T.; Han, I.; Wu, L.; Zeng, X. |
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Title |
Targeted Nanotechnology in Glioblastoma Multiforme |
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Journal Article |
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2017 |
Publication |
Frontiers in Pharmacology |
Abbreviated Journal |
Front Pharmacol |
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8 |
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166 |
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Keywords |
blood-brain barrier; cancer stem cell; glioma; nanomedicine; nanotechnology; targeted therapy |
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Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs. |
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Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen UniversityGuangzhou, China |
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1663-9812 |
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PMID:28408882 |
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ref @ user @ |
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96596 |
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Author |
Foro Arnalot, P.; Pera, O.; Rodriguez, N.; Sanz, X.; Reig, A.; Membrive, I.; Ortiz, A.; Granados, R.; Algara, M. |
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Title |
Influence of incidental radiation dose in the subventricular zone on survival in patients with glioblastoma multiforme treated with surgery, radiotherapy, and temozolomide |
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Journal Article |
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Year |
2017 |
Publication |
Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico |
Abbreviated Journal |
Clin Transl Oncol |
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Glioblastoma; Radiotherapy; Subventricular zone |
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PURPOSE: To determine if there is an association between the incidental radiation dose to the subventricular zone and survival in patients with glioblastoma multiforme treated with surgery, radiotherapy and temozolomide. METHODS AND MATERIALS: Sixty-five patients, treated between 2006 and 2015, were included in this retrospective study. The doses (75th percentile; p75) administered to the ipsilateral, contralateral and bilateral subventricular zone were compared to overall survival and progression-free survival using Cox proportional hazards models. Covariates included: age, sex, surgery, tumor location, and concomitant and adjuvant temozolomide. RESULTS: Median progression-free survival and overall survival were 11.5 +/- 9.96 and 18.8 +/- 18.5 months, respectively. The p75 doses to the ipsilateral, contralateral and bilateral subventrivular zone were, respectively, 57.30, 48.8, and 52.7 Gy. Patients who received a dose >/=48.8 Gy in the contralateral subventricular zone had better progression-free survival than those who received lower doses (HR 0.46; 95% CI 0.23-0.91 P = 0.028). This association was not found for overall survival (HR 0.60; 95% CI 0.30-1.22 P = 0.16). Administration of adjuvant temozolomide was significantly associated with improved progression-free survival (HR 0.19; 95% CI 0.09-0.41 P < 0.0001) and overall survival (HR 0.11; 95% CI 0.05-0.24 P = 0.001). In the subgroup of 46 patients whose O6-methylguanine-DNA methyltransferase gene promoter status was known, the methylation had no effect on either progression-free survival (P = 0.491) or overall survival (P = 0.203). CONCLUSION: High-dose radiation in the contralateral subventricular zone was associated with a significant improvement in progression-free survival but not overall survival in patients treated for glioblastoma multiforme. |
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Universitat Pompeu Fabra, Barcelona, Spain |
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1699-048X |
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PMID:28389881 |
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ref @ user @ |
Serial |
96597 |
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de Sousa, J.F.; Torrieri, R.; Serafim, R.B.; Di Cristofaro, L.F.M.; Escanfella, F.D.; Ribeiro, R.; Zanette, D.L.; Paco-Larson, M.L.; da Silva, W.A.J.; Tirapelli, D.P. da C.; Neder, L.; Carlotti, C.G.J.; Valente, V. |
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Title |
Expression signatures of DNA repair genes correlate with survival prognosis of astrocytoma patients |
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Journal Article |
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Year |
2017 |
Publication |
Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine |
Abbreviated Journal |
Tumour Biol |
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Volume |
39 |
Issue |
4 |
Pages |
1010428317694552 |
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Keywords |
Apoptosis; Astrocytoma/genetics/metabolism/*mortality; Brain Neoplasms/genetics/metabolism/*mortality; Cell Cycle; Cell Line, Tumor; *DNA Repair; DNA Repair Enzymes/genetics/metabolism; Exodeoxyribonucleases/genetics/metabolism; Gene Expression; Humans; Kaplan-Meier Estimate; N-Glycosyl Hydrolases/genetics/metabolism; Prognosis; DNA repair; astrocytoma; genomic instability; glioblastoma; tumor progression |
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Astrocytomas are the most common primary brain tumors. They are very resistant to therapies and usually progress rapidly to high-grade lesions. Here, we investigated the potential role of DNA repair genes in astrocytoma progression and resistance. To this aim, we performed a polymerase chain reaction array-based analysis focused on DNA repair genes and searched for correlations between expression patters and survival prognoses. We found 19 genes significantly altered. Combining these genes in all possible arrangements, we found 421 expression signatures strongly associated with poor survival. Importantly, five genes (DDB2, EXO1, NEIL3, BRCA2, and BRIP1) were independently correlated with worse prognoses, revealing single-gene signatures. Moreover, silencing of EXO1, which is remarkably overexpressed, promoted faster restoration of double-strand breaks, while NEIL3 knockdown, also highly overexpressed, caused an increment in DNA damage and cell death after irradiation of glioblastoma cells. These results disclose the importance of DNA repair pathways for the maintenance of genomic stability of high-grade astrocytomas and suggest that EXO1 and NEIL3 overexpression confers more efficiency for double-strand break repair and resistance to reactive oxygen species, respectively. Thereby, we highlight these two genes as potentially related with tumor aggressiveness and promising candidates as novel therapeutic targets. |
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7 Center for Integrative Systems Biology (CISBi), NAP/USP, Ribeirao Preto, Brazil |
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1010-4283 |
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PMID:28378638 |
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Call Number |
ref @ user @ |
Serial |
96598 |
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