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  • Directory of Open Access Journals (DOAJ)  (6)
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  • 1
    Language: English
    In: Cell Reports, 29 March 2016, Vol.14(12), pp.2925-2937
    Description: How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using mice to study medulloblastoma progression, we found that loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic mutations or locus inactivation. Consistent with senescence evasion, these mutations are always subsequent to LOH. Introduction of a mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with LOH allows progression to advanced tumors. How brain tumors develop from precancerous lesions is not well understood. Using heterozygous mice, Tamayo-Orrego et al. show that medulloblastoma preneoplastic lesions display loss of heterozygosity and cell senescence, a tumor-suppressive mechanism. Subsequently, spontaneous mutations or inactivation leads to senescence evasion and medulloblastoma progression.
    Keywords: Medulloblastoma ; Sonic Hedgehog ; Ptch1 ; Preneoplasia ; Cerebellum ; P53 ; P16ink4a ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 2
    Language: English
    In: International journal of molecular sciences, 08 April 2013, Vol.14(4), pp.7492-505
    Description: Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. We studied the expression of Dickkopf (DKK) 1-4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p 〈 0.001). Since copy number aberrations targeting the DKK3 locus (11p15.3) are rare events, we hypothesized that epigenetic factors could play a role in DKK3 regulation. Accordingly, we studied 77 miRNAs predicting to repress DKK3; however, no significant inverse correlation between miRNA/mRNA expression was observed. Moreover, the low methylation levels in the DKK3 promoters (median: 3%, 5% and 5% for promoter 1, 2 and 3, respectively) excluded the downregulation of gene expression by methylation. On the other hand, the treatment of MB cells with Trichostatin A (TSA), a potent inhibitor of histone deacetylases (HDAC), was able to restore both DKK3 mRNA and protein. In conclusion, DKK3 downregulation across all MB subgroups may be due to epigenetic mechanisms, in particular, through chromatin condensation.
    Keywords: Chromatin Assembly and Disassembly ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Intercellular Signaling Peptides and Proteins -- Biosynthesis ; Medulloblastoma -- Metabolism ; Neoplasm Proteins -- Biosynthesis
    ISSN: 1422-0067
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  • 3
    Language: English
    In: Journal of neurosurgery, December 2014, Vol.121(6), pp.1433
    Description: Malignant astrocytomas are the most common and highly vascularized of all primary adult brain tumors. The histopathological hallmarks of malignant astrocytomas are microvascular proliferation and formation of vascular entities, which are referred to as "glomeruloid bodies." The significance of glomeruloid bodies and the molecular mechanisms driving the abnormal vascular architecture in malignant astrocytomas are not understood. We have observed that overexpression of angiopoietin-1 (Ang1) in both subcutaneous and intracranial xenograft models of malignant astrocytomas reproduces many of the vascular features of these tumors, including glomeruloid bodies. To confirm that the formation of glomeruloid bodies was directly dependent on Ang1, we performed experiments where levels of Ang1 expression were regulated under tetracycline control, and we found a direct correlation between levels of Ang1 expression and the occurrence of glomeruloid bodies in xenografts. Additionally, we inhibited the action of Ang1 by blocking its cognate receptor Tie2, and we found that the formation of glomeruloid bodies was inhibited. Collectively, these results support our hypothesis that Ang1 is a key molecular regulator of pathological vascularization characteristic of malignant astrocytomas.
    Keywords: Gene Expression Regulation, Neoplastic -- Physiology ; Neuroma, Acoustic -- Genetics ; Signal Transduction -- Physiology ; Vestibular Nerve -- Physiology
    ISSN: 15228002
    E-ISSN: 1933-0693
    E-ISSN: 14765586
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2019, Vol.14(1), p.e0210665
    Description: High morbidity and mortality are common traits of malignant tumours and identification of the cells responsible is a focus of on-going research. Many studies are now reporting the use of antibodies specific to Clusters of Differentiation (CD)...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Cancers, 01 November 2019, Vol.11(11), p.1702
    Description: Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae...
    Keywords: Stat3 ; Sexual Dimorphism ; Medulloblastoma ; Sonic Hedgehog ; Medicine
    E-ISSN: 2072-6694
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  • 6
    Language: English
    In: Cell Death and Disease, 01 March 2019, Vol.10(3), pp.1-14
    Description: Abstract Glioblastoma multiform (GBM) is the most common brain tumor characterized by a dismal prognosis. GBM cancer stem cells (gCSC) or tumor-initiating cells are the cell population within the tumor-driving therapy resistance and recurrence. While temozolomide (TMZ), an alkylating agent, constitutes the first-line chemotherapeutic significantly improving survival in GBM patients, resistance against this compound commonly leads to GBM recurrence and treatment failure. Although the roles of protein-coding transcripts, proteins and microRNA in gCSC, and therapy resistance have been comprehensively investigated, very little is known about the role of long noncoding RNAs (lncRNAs) in this context. Using nonoverlapping, independent RNA sequencing and gene expression profiling datasets, we reveal that TP73-AS1 constitutes a clinically relevant lncRNA in GBM. Specifically, we demonstrate significant overexpression of TP73-AS1 in primary GBM samples, which is particularly increased in the gCSC. More importantly, we demonstrate that TP73-AS1 comprises a prognostic biomarker in glioma and in GBM with high expression identifying patients with particularly poor prognosis. Using CRISPRi to downregulate our candidate lncRNA in gCSC, we demonstrate that TP73-AS1 promotes TMZ resistance in gCSC and is linked to regulation of the expression of metabolism- related genes and ALDH1A1, a protein known to be expressed in cancer stem cell markers and protects gCSC from TMZ treatment. Taken together, our results reveal that high TP73-AS1 predicts poor prognosis in primary GBM cohorts and that this lncRNA promotes tumor aggressiveness and TMZ resistance in gCSC.
    Keywords: Biology
    E-ISSN: 2041-4889
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