Abstract
Glioblastoma multiforme (GBM) is the most aggressive brain tumor, with a 5-year survival ratio <5%. Invasive growth is a major determinant of the poor prognosis in GBM. In this study, we demonstrate that high expression of PPFIA binding protein 1 (PPFIBP1) correlates with remarkable invasion and poor prognosis of GBM patients. Using scratch and transwell assay, we find that the invasion and migration of GBM cells are promoted by overexpression of PPFIBP1, while inhibited by knockdown of PPFIBP1. Then, we illustrate that overexpression of PPFIBP1 facilitates glioma cell infiltration and reduces survival in xenograft models. Next, RNA-Seq and GO enrichment analysis reveal that PPFIBP1 regulates differentially expressed gene clusters involved in the Wnt and adhesion-related signaling pathways. Furthermore, we demonstrate that PPFIBP1 activates focal adhesion kinase (FAK), Src, c-Jun N-terminal kinase (JNK), and c-Jun, thereby enhancing Matrix metalloproteinase (MMP)-2 expression probably through interacting with SRCIN1 (p140Cap). Finally, inhibition of phosphorylation of Src and FAK significantly reversed the augmentation of invasion and migration caused by PPFIBP1 overexpression in GBM cells. In conclusion, these findings uncover a novel mechanism of glioma invasion and identify PPFIBP1 as a potential therapeutic target of glioma.
Highlights
Gliomas are the most common aggressive primary brain tumors, of which glioblastoma multiforme (GBM) is the most malignant form (WHO grade IV) in human
High expression of PPFIA binding protein 1 (PPFIBP1) in glioma correlates with increased invasion and poor prognosis of patients Immunohistochemical (IHC) staining on tumor tissues from patients were performed to investigate the relationship between PPFIBP1 protein levels and the aggressiveness of glioma
The results indicated that PPFIBP1 protein levels in GBM tissues (14/23, 61%) were significantly higher than that in low-grade glioma (LGG) (6/24, 25%) (P = 0.041, Fig. 1A), and higher in invasive LGG tissues (3/10, 30%) than in noninvasive LGG tissues (3/14, 21%), not statistically significant (Fig. 1B)
Summary
Gliomas are the most common aggressive primary brain tumors, of which glioblastoma multiforme (GBM) is the most malignant form (WHO grade IV) in human. The past decade has witnessed essential progress in understanding of glioma cell invasion. Aggressive glioma cells vigorously migrate through the tortuous extracellular spaces of the brain, resulting in the formation of distant satellite tumors [5]. Cell migration involves four distinct steps: (1) leading edge protrusion, (2) turnover of focal adhesions, (3) generation of tractional forces, and (4) tail retraction and detachment [7,8,9]. Previous studies have revealed that Src and FAK promoted focal adhesion turnover during transformation and migration, which is indispensable for cell migration on extracellular matrix [10,11,12]
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