SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties.
OBJECTIVE
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.
Pediatric Oncology Institute/GRAACC, Department of Pediatrics, Federal University of São Paulo, São Paulo, SP, Brazil, brunamascaro@gmail.com.
Bruna Mascaro
BM
Cordeiro
Indhira Dias
ID
Oliveira
Maria Teresa de Seixas
MT
Alves
Nasjla
N
Saba-Silva
Andrea M
AM
Capellano
Sergio
S
Cavalheiro
Patrícia
P
Dastoli
Silvia Regina Caminada
SR
Toledo
D002454:Cell Differentiation; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome; D051153:Wnt Proteins / Q000378:metabolism*
D053823:Hedgehog Proteins; D051880:Receptors, Notch; C509239:SHH protein, human; D051153:Wnt Proteins