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SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties

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Abstract

Purpose

Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics.

Methods

We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient’s clinicopathological characteristics.

Results

Considering the universal RNA as our control sample, and considering the median of gene expression in the control samples as our cutoff, we observed that HES1 gene showed decreased expression compared to control (p = 0.0059), but patients with HES1 overexpression were directly related to a shorter survival (p = 0.0165). Individuals with higher GLI1 gene expression had significant shorter survival (p = 0.0469), and high expression was prevalent in patients up to 5 years old (p = 0.0479). Patients showing high PTCH2 expression were related to worse survival (p = 0.0426), and it was correlated with GLI1 high expression (p = 0.0094). We also observed a concomitant overexpression of WIF1 and DKK2 genes in a subgroup of MB samples (n = 11, p = 0.0118).

Conclusions

Our results suggest the presence of activated developmental signaling pathways in MB, which are important for cell proliferation and maintenance, and that may be targeted for novel therapeutic options.

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Acknowledgments

This work was supported by grants from FAPESP (The State of São Paulo Research Foundation: 2011/19629-0; 2011/16221-0) and GRAACC (Grupo de Apoio ao Adolescente e Criança com Câncer).

Ethical standards

Samples from each MB tumor were collected after informed consent was signed by patients/guardians according to the university’s institutional review board (IRB/Federal University of São Paulo no. 0474/11).

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Authors and Affiliations

  1. Pediatric Oncology Institute/GRAACC, Department of Pediatrics, Federal University of São Paulo, São Paulo, SP, Brazil

    Bruna Mascaro Cordeiro, Indhira Dias Oliveira, Maria Teresa de Seixas Alves, Nasjla Saba-Silva, Andrea M. Capellano, Sergio Cavalheiro, Patrícia Dastoli & Silvia Regina Caminada Toledo

  2. Department of Morphology and Genetics, Division of Genetics, Federal University of São Paulo, São Paulo, SP, Brazil

    Bruna Mascaro Cordeiro, Indhira Dias Oliveira & Silvia Regina Caminada Toledo

  3. Department of Pathology, Federal University of São Paulo, São Paulo, SP, Brazil

    Maria Teresa de Seixas Alves

  4. Department of Neurology, Federal University of São Paulo, São Paulo, SP, Brazil

    Sergio Cavalheiro

  5. Pediatrics Oncology Institute-GRAACC (Grupo de Apoio ao Adolescente e à Criança com Câncer)/UNIFESP (Federal University of São Paulo), Rua Botucatu, no. 743, Floor 8, Genetics Laboratory, Vila Clementino, São Paulo, SP, Brazil, 04023-062

    Silvia Regina Caminada Toledo

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  1. Bruna Mascaro Cordeiro
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  2. Indhira Dias Oliveira
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Correspondence to Silvia Regina Caminada Toledo.

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Mascaro Cordeiro, B., Dias Oliveira, I., de Seixas Alves, M.T. et al. SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties. Childs Nerv Syst 30, 1165–1172 (2014). https://doi.org/10.1007/s00381-014-2403-x

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  • DOI: https://doi.org/10.1007/s00381-014-2403-x

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