| Popis: |
Only 2% of Glioblastoma multiforme (GBM) patients respond to standard care and survive beyond 36 months (long-term survivors, LTS) while the majority survives less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that co-occur with aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the GO-categories “epithelial to mesenchymal transition” and “response to hypoxia”. Promoter and network analysis of the DEGs identified 5 potential master regulators that may explain dysregulation of the DEGs in the STS. The following 5 important master-regulators were identified: IGFBP2, VEGFA, PDGFA, OSMR and AEBP1. It is known that IGFBP2 confers increasing malignancy leading to poor prognosis. However, the molecular mechanism by which IGFBP2 affects disease progression and patient prognosis is unclear. Here we found that IGFBP2 is highly upregulated in short survivors and significantly impact survival. Further investigation of the gene regulatory network revealed that IGFBP2 expression can be regulated by FRA-1 transcription factor via MEK2/RAF/ERK5 pathway. FRA-1 is found to be upregulated and to have significant impact on survival in GBM. It is previously reported that FRA-1 can dysregulate at-least 50 genes involved in tumor invasiveness in tumor xenografts making it a therapeutic target for GBM intervention. We propose that IGFBP2 drives dysregulated gene network responsible for short survival in GBM via FRA-1 transcription factor. |
