RESUMO
Somatic and germline duplications or activating mutations of AKT3 have been reported in patients with hemimegalencephaly and megalencephaly. We performed array comparative genomic hybridization on brain tissue and blood in 16 consecutive patients with symptomatic epilepsy due to focal or multilobar malformations of cortical development who underwent surgical treatment of epilepsy. One patient with infantile spasms and a dysplastic left frontal lobe harboured a somatic trisomy of the 1q21.1-q44 chromosomal region, encompassing the AKT3 gene, in the dysplastic brain tissue but not in blood and saliva. Histopathology revealed severe cortical dyslamination, a thin cortex in the premotor area with microgyri and microsulci, immature neurons with disoriented dendrites and areas of cortical heterotopia in the sub-cortical white matter. These cytoarchitectural changes are close to those defining type Ib focal cortical dysplasia. Immunohistochemistry in brain specimens showed hyperactivation of the PI3K/AKT/mTOR pathway. These findings indicate that AKT3 upregulation may cause focal malformations of cortical development. There appears to be an etiologic continuum between hemimegalencephaly and focal cortical dysplastic lesions. The extent of brain malformations due to AKT3 upregulation may be related to the embryonic stage when the post-zygotic gene alteration occurs.
Assuntos
Córtex Cerebral/patologia , Duplicação Cromossômica , Cromossomos Humanos Par 1 , Proteínas Proto-Oncogênicas c-akt/genética , Espasmos Infantis/genética , Espasmos Infantis/patologia , Criança , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Repetições de Microssatélites , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espasmos Infantis/diagnósticoRESUMO
Cancer stem cell (CSC), the primary source of cancer-initiating population, is involved in cancer recurrence and drug-resistant phenotypes. This study demonstrates that the loss of DAB2IP, a novel Ras-GTPase activating protein frequently found in many cancer types, is associated with CSC properties. Mechanistically, DAB2IP is able to suppress stem cell factor receptor (c-kit or CD117) gene expression by interacting with a newly identified silencer in the c-kit gene. Moreover, DAB2IP is able to inhibit c-kit-PI3K-Akt-mTOR signaling pathway that increases c-myc protein to activate ZEB1 gene expression leading to the elevated CSC phenotypes. An inverse correlation between CD117 or ZEB1 and DAB2IP is also found in clinical specimens. Similarly, Elevated expression of ZEB1 and CD117 are found in the prostate basal cell population of DAB2IP knockout mice. Our study reveals that DAB2IP has a critical role in modulating CSC properties via CD117-mediated ZEB1 signaling pathway.
