Abstract
Glioblastoma (GBM) is characterized by the presence of hypoxia, stemness and local invasiveness. We have earlier demonstrated that FAT1 promotes invasiveness, inflammation and upregulates HIF-1α expression and its signalling in hypoxic GBM. Here, we have identified the role of FAT1 in regulating EMT (Epithelial-Mesenchymal Transition) and stemness characteristics in GBM. The expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/VEGF/PGK1/CA9) was upregulated in ≥39% of GBM tumors (n=31) with significant positive correlation (p≤0.05) of the expression of FAT1 with LOX/Vimentin/SOX2/HIF-1α/PGK1/VEGF/CA9. Furthermore, positive correlation (p≤0.01) of FAT1 with Vimentin/N-cad/SOX2/REST/HIF-1α has been observed in TCGA GBM-dataset (n=430). Analysis of cells (U87MG/A172) exposed to severe hypoxia (0.2%O2) revealed elevated mRNA expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/PGK1/VEGF/CA9) as compared to their normoxic (20%O2) counterparts. FAT1 knockdown in U87MG/A172 maintained in severe hypoxia and in normoxic primary glioma cultures led to significant reduction of EMT/stemness markers as compared to controls. HIF-1α knockdown in U87MG cells markedly reduced the expression of all the EMT/stemness markers studied except for nestin and SOX2 which were more under the influence of FAT1. This indicates FAT1 has a novel regulatory effect on EMT/stemness markers both via or independent of HIF-1α. The functional relevance of our study was corroborated by significant reduction in the number of soft-agar colonies formed in hypoxic-siFAT1 treated U87MG cells. Hence, this study for the first time reveals FAT1 as a novel regulator of EMT/stemness in hypoxic GBM and suggests FAT1 as a potential therapeutic candidate. This article is protected by copyright. All rights reserved.
from Cancer via ola Kala on Inoreader http://ift.tt/2fXyGAL
via IFTTT
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου