Wnt activation affects proliferation, invasiveness and radiosensitivity in medulloblastoma

Abstract

Medulloblastomas (MBs) associated with the Wnt activation represent a subgroup with a favorable prognosis, but it remains unclear whether Wnt activation confers a less aggressive phenotype and/or enhances radiosensitivity. To investigate this issue, we evaluated the biological behavior of an MB cell line, UW228-1, stably transfected with human β-catenin cDNA encoding a nondegradable form of β-catenin (UW-B) in standard culture conditions and after radiation treatment. We evaluated the expression, transcriptional activity, and localization of β-catenin in the stably transfected cells using immunofluorescence and WB. We performed morphological analysis using light and electron microscopy. We then analyzed changes in the invasiveness, growth, and mortality in standard culture conditions and after radiation. We demonstrated that (A) Wnt activation inhibited 97 % of the invasion capability of the cells, (B) the growth of the UW-B cells was statistically significantly lower than that of all the other control cells (p < 0.01), (C) the mortality of irradiated UW-B cells was statistically significantly higher than that of the controls and their nonirradiated counterparts (p < 0.05), and (D) morphological features of neuronal differentiation were observed in the Wnt-activated cells. In tissue samples, the Ki-67 labeling index (LI) was lower in β-catenin-positive samples compared to non-β-catenin positive ones. The Ki-67 LI median (LI = 40) of the nuclear β-catenin-positive tumor samples was lower than that of non-nuclear β-catenin-positive samples (LI = 50), but the difference was not statistically significant. Overall, our data suggest that activation of the Wnt pathway reduces the proliferation and invasion of MBs and increases the tumor's radiosensitivity.

WISP1 Polymorphisms Contribute to Platinum-Based Chemotherapy Toxicity in Lung Cancer Patients

“…The Wnt signaling pathway regulates the transcription of many genes that are involved in cell proliferation, differentiation and the prevalence of cancers [ 20 , 21 , 22 ]. The canonical Wnt-β-catenin pathway is one of the three major Wnt signaling pathways, and it is involved in diverse cancers, such as hepatocellular carcinoma and esophageal squamous carcinoma [ 23 , 24 ].…”

β-catenin knockdown inhibits pituitary adenoma cell proliferation and invasion via interfering with AKT and gelatinases expression

“…The accumulation of β-catenin in the cytoplasm leads to its translocation into the nucleus and binding to TCF/LEF transcription factors to regulate several target genes (19). Increasing evidence suggests that excessive accumulation of β-catenin is involved in tumor invasion and proliferation (20)(21)(22). In human colorectal cancer, β-catenin expression levels are found to be associated with aggressive morphological features, epithelial-mesenchymal transition and a poor prognosis (23).…”

Estudo da modulação da via Wnt pelo inibidor de Aurora-quinases AMG900 em linhagens celulares de meduloblastoma pediátrico

“…No entanto, devido à pequena coorte de MB tipo Wnt, e pelo fato de esta ser uma neoplasia bastante rara e com um prognóstico favorável, linhagens celulares de MB Wnt ainda não foram imortalizadas, não estando disponíveis para estudos. Como ainda não está claro se a ativação da via Wnt pode conferir um genótipo menos agressivo em MB são necessárias mais investigações nesse subgrupo molecular (Salaroli et al, 2015).…”

“…A elevada expressão de βcatenina (CTNNB1) nos cerebelos não neoplásicos já era esperada, visto que esta proteína tem um papel importante em outras atividades celulares, como nas junções celulares contendo caderina e na motilidade celular (Gilbertson, 2004;Rossi et al, 2008). Salaroli et al, 2015).…”

“…Ciclina D1 e C-myc em linhagens de meduloblastoma. É interessante ressaltar que a expressão dos genes Aurora-A e Aurora-B nessas linhagens não foi alterada após a transfecção, indicando que não há uma correlação da expressão gênica da β-catenina com a dos genes Aurora-A e Aurora-B Salaroli et al (2015). relataram uma redução no número de colônias após transfectar células de meduloblastoma com o plasmídeo pCI-neo/b-catenin S33Y.…”