Prognostic value of <i>SOX2</i> expression in neuroblastoma

Gómez-Mateo, María del Carmen; Piqueras, Marta; Påhlman, Sven; Noguera, Rosa; Navarro, Samuel

doi:10.1002/gcc.20859

Cited by 12 publications

(7 citation statements)

References 21 publications

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“…However, there was no change in the levels of TUBB3 at this time point in either cell lines (Supplementary Figure S8c). Interestingly, SOX2 over-expression in the n = 88 tumor set is significant for poor OS and EFS with one probe (Supplementary Figure S8d,e), consistent with findings at protein level (39). …”

Section: Resultssupporting

confidence: 83%

Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs

et al. 2012

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MicroRNAs contribute to the pathogenesis of many forms of cancer, including the pediatric cancer neuroblastoma, but the underlying mechanisms leading to altered miRNA expression are often unknown. Here, a novel integrated approach for analyzing DNA methylation coupled with miRNA and mRNA expression data sets identified 67 epigenetically regulated miRNA in neuroblastoma. A large proportion (42%) of these miRNAs were associated with poor patient survival when under-expressed in tumors. Moreover, we demonstrate that this panel of epigenetically silenced miRNAs targets a large set of genes that are over-expressed in tumors from patients with poor survival in a highly redundant manner. The genes targeted by the epigenetically regulated miRNAs are enriched for a number of biological processes, including regulation of cell differentiation. Functional studies involving ectopic over-expression of several of the epigenetically silenced miRNAs had a negative impact on neuroblastoma cell viability, providing further support to the concept that inactivation of these miRNAs is important for neuroblastoma disease pathogenesis. One locus, miR-340, induced either differentiation or apoptosis in a cell context dependent manner, indicating a tumor suppressive function for this miRNA. Intriguingly, it was determined that miR-340 is up-regulated by demethylation of an upstream genomic region that occurs during the process of neuroblastoma cell differentiation induced by all-trans retinoic acid (ATRA). Further biological studies of miR-340 revealed that it directly represses the SOX2 transcription factor by targeting of its 3’ UTR, explaining the mechanism by which SOX2 is down-regulated by ATRA. Although SOX2 contributes to the maintenance of stem cells in an undifferentiated state, we demonstrate that miR-340 mediated down-regulation of SOX2 is not required for ATRA induced differentiation to occur. In summary, our results exemplify the dynamic nature of the miRNA epigenome and identify a remarkable network of miRNA/mRNA interactions that significantly contribute to neuroblastoma disease pathogenesis.

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Section: Resultssupporting

confidence: 83%

Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs

et al. 2012

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“…Melone et al detected the expression of Oct4 in NB cells and tissue samples, but Sox2 expression was not found (29). Gomez-Mateo et al evaluated the expression and clinical significance of Sox2 in NB using immunohistochemical staining and found that high Sox2 protein levels correlate to aggressive disease, indicating that Sox2 protein levels may be an important prognostic indicator of NB (30). However, in the present study for the first time, we investigated the expression of Oct4 and Sox2 in paired NB tissues and matched adjacent non-cancerous tissues and investigated their relationship with clinicopathological parameters.…”

Section: Discussionmentioning

confidence: 99%

Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy

Yang

Zheng

et al. 2012

Oncol Rep

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Abstract. Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy. Oct4 and Sox2 are essential transcription factors for embryonic development and play key roles in determining the fate of stem cells. In this study, we aimed to investigate the expression of Oct4 and Sox2 in NB tissues, and evaluated their relationship with various clinicopathological parameters. Oct4 and Sox2 expression in 65 samples of NB and paracancerous tissues was examined by real-time PCR. The relationship between Oct4 and Sox2 expression and clinical data was assessed. To detect Oct4 and Sox2 expression at the protein level, western blot analyses and immunohistochemical staining were employed. We found that the expression levels of Oct4 and Sox2 in NB tissues were significantly higher than those in paracancerous tissues (P<0.05). Oct4 and Sox2 expression was significantly correlated to the clinical stage of NB, but not other clinicopathological parameters including patient gender and age, tumor size, location and histological classification. In stage III and IV tumors, Oct4 and Sox2 expression was significantly decreased in the chemotherapy subgroup as compared with that of the non-chemotherapy subgroup (P<0.05). These findings suggest that the expression of Oct4 and Sox2 may correlate with the genesis and progression of NB. In addition, Oct4 and Sox2 expression can be inhibited by chemotherapy.

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“…Given the importance of neuroblastoma interactions with ECM proteins 38 , the 3D cultures in hydrogels could better mimic the in vivo situation than the floating spheroid models widely used in cancer biology [39][40][41] . Furthermore, the hydrogel environment appeared to modulate expression of neural markers, CD133 and SOX2, which are also considered markers of "stemness" of tumour initiating cells, and are important prognostic markers of neuroblastoma progression and development [42][43][44][45] . Together, 3D cultures of undifferentiated neuroblastoma cells seem to be a more suitable model for cancer cell development than injury response studies.…”

Section: Discussionmentioning

confidence: 99%

Modelling human CNS injury with human neural stem cells in 2- and 3-Dimensional cultures

Vagaska

Gillham

Ferretti

2020

Sci Rep

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The adult human central nervous system (CNS) has very limited regenerative capability, and injury at the cellular and molecular level cannot be studied in vivo. Modelling neural damage in human systems is crucial to identifying species-specific responses to injury and potentially neurotoxic compounds leading to development of more effective neuroprotective agents. Hence we developed human neural stem cell (hNSC) 3-dimensional (3D) cultures and tested their potential for modelling neural insults, including hypoxic-ischaemic and Ca 2+ -dependent injury. Standard 3D conditions for rodent cells support neuroblastoma lines used as human CNS models, but not hNSCs, but in all cases changes in culture architecture alter gene expression. Importantly, response to damage differs in 2D and 3D cultures and this is not due to reduced drug accessibility. Together, this study highlights the impact of culture cytoarchitecture on hNSC phenotype and damage response, indicating that 3D models may be better predictors of in vivo response to damage and compound toxicity.In light of the practical and ethical limitations of human research, animal models provide fundamental insight into the central nervous system (CNS) development, injury, disease, as well as the possibility of studying and screening putative therapeutic compounds. However, there is an increasing appreciation of the limitations of animal research, which often fails to reliably predict successful human clinical trials. Key examples of this are hypoxia-ischemia either in newborns (1-8 cases per 1000 births in the Western world) or adults (cerebral stroke) and traumatic injuries to the CNS 1-3 . While animal models have significantly furthered understanding of the mechanisms of injury and repair, and various neuroprotective agents have proven effective in animal injury models, this has not translated into effective treatments in humans 4-6 . Such failures to translate animal studies to successful human clinical trials are often attributed to problems with methodological and study design. However, species-specific differences in drug processing, genetic interactions and molecular mechanisms of action can be argued to be fundamental to therapeutic translation. Further studies on the cell ular mechanisms of human CNS injury and repair are therefore needed in order to develop better therapeutic strategies and bridge the gap between animal models and human clinical trials 7,8 .Three dimensional (3D) culture models have been rapidly emerging as a means to study human cells in vitro. While still in many respects rather challenging, because more complex to maintain and analyse, they reduce the strain and artificial responses which cells must undergo in order to adapt to the flat, stiff surfaces of 2D monolayer culture. A 3D architecture provides a more tissue-like environment in which cell-cell and cell-matrix interact in all dimensions and cells have more biologically relevant exposure to diffusible factors 9,10 . Whereas the use of iPSCs (induced pluripotent stem cells) derived f...

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Prognostic value of SOX2 expression in neuroblastoma

Cited by 12 publications

References 21 publications

Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs

Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs

Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy

Modelling human CNS injury with human neural stem cells in 2- and 3-Dimensional cultures

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