Abstract
Glioblastoma (GBM) is a highly aggressive brain cancer with poor prognosis and low survival rate. Invasive cancer stem-like cells (CSCs) are responsible for tumor recurrence because they escape current treatments. Our main goal was to study the proteome of three GBM subpopulations to identify key molecules behind GBM cell phenotypes and potential cell markers for migrating cells. We used SuperQuant–an enhanced quantitative proteome approach–to increase proteome coverage. We found 148 proteins differentially regulated in migrating CSCs and 199 proteins differentially regulated in differentiated cells. We used Ingenuity Pathway Analysis (IPA) to predict upstream regulators, downstream effects and canonical pathways associated with regulated proteins. IPA analysis predicted activation of integrin-linked kinase (ILK) signaling, actin cytoskeleton signaling, and lysine demethylase 5B (KDM5B) in CSC migration. Moreover, our data suggested that microRNA-122 (miR-122) is a potential upstream regulator of GBM phenotypes as miR-122 activation was predicted for differentiated cells while its inhibition was predicted for migrating CSCs. Finally, we validated transferrin (TF) and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) as potential markers for migrating cells.
Highlights
Glioblastoma (GBM), a WHO grade IV glioma, is the most aggressive primary brain cancer [1] with a median survival rate of only 15 months [2]
We found 148 proteins differentially regulated in migrating cancer stem-like cells (CSCs) and 199 proteins differentially regulated in differentiated cells
Experimental design used to study proteins involved in the GBM migration and differentiation We used the proteomics pipeline represented in Figure 1 to compare the proteome of three GBM cell phenotypes
Summary
Glioblastoma (GBM), a WHO grade IV glioma, is the most aggressive primary brain cancer [1] with a median survival rate of only 15 months [2]. Surgical resection combined with radiotherapy and chemotherapy is the standard treatment for GBM [2]. Tumor recurrence is inevitable because GBM cells can invade surrounding tissues preventing full removal of tumor cells by resection. Subpopulations of cancer stem-like cells (CSCs), which are resistant to radiotherapy and chemotherapy, are present in tumor environment [3, 4]. Evidences suggest that CSCs have developed a number of molecular mechanisms to escape and survive treatments. Radiotherapy with concomitant temozolomide (TMZ) has increased the survival rate by several months [2], recurrence is still observed after treatment
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