SHP-2-upregulated ZEB1 is important for PDGFRα-driven glioma epithelial–mesenchymal transition and invasion in mice and humans

Abstract

Gliomas are highly malignant brain tumors that are highly invasive and resistant to conventional therapy. Receptor tyrosine kinases (RTKs) such as PDGFRα (platelet-derived growth factor receptor-α), which show frequent aberrant activation in gliomas, are associated with a process of epithelial–mesenchymal transition (EMT), a cellular alteration that confers a more invasive and drug-resistant phenotype. Although this phenomenon is well documented in human cancers, the processes by which RTKs including PDGFRα mediate EMT are largely unknown. Here, we report that SHP-2 (encoded by PTPN11) upregulates an EMT inducer, ZEB1, to mediate PDGFRα-driven glioma EMT, invasion and growth in glioma cell lines and patient-derived glioma stem cells (GSCs) using cell culture and orthotopic xenograft models. ZEB1 and activated PDGFRα were coexpressed in invasive regions of mouse glioma xenografts and clinical glioma specimens. Glioma patients with high levels of both phospho-PDGFRα (p-PDGFRα) and ZEB1 had significantly shorter overall survival compared with those with low expression of p-PDGFRα and ZEB1. Knockdown of ZEB1 inhibited PDGFA/PDGFRα-stimulated glioma EMT, tumor growth and invasion in glioma cell lines and patient-derived GSCs. PDGFRα mutant deficient of SHP2 binding (PDGFRα-F720) or phosphoinositide 3-kinase (PI3K) binding (PDGFRα-F731/42), knockdown of SHP2 or treatments of pharmacological inhibitor for PDGFRα-signaling effectors attenuated PDGFA/PDGFRα-stimulated ZEB1 expression, cell migration and GSC proliferation. Importantly, SHP-2 acts together with PI3K/AKT to regulate a ZEB1-miR-200 feedback loop in PDGFRα-driven gliomas. Taken together, our findings uncover a new pathway in which ZEB1 functions as a key regulator for PDGFRα-driven glioma EMT, invasiveness and growth, suggesting that ZEB1 is a promising therapeutic target for treating gliomas with high PDGFRα activation.

Molecular Mechanisms of Glioma Cell Motility

“…ZEB-1 and PDGFRa were found to be co-expressed in tissue samples from GBM patients, while high expression of both ZEB-1 and activated PDGFRa was identified to significantly coincide with poor survival. The same study further established Protein Tyrosine Phosphatase/Nonreceptor type (PTPN)-1 as a regulator of ZEB-1-induced and PDGFR-induced EMT in glioma (170). EMT may also be directly promoted by the microenvironment of GBM.…”

PIK3R3 Promotes Metastasis of Pancreatic Cancer via ZEB1 Induced Epithelial-Mesenchymal Transition

“…Some transcriptional factors could bind to the promoter region of E-Cadherin to suppress its expression, and further trigger the EMT conversion and metastasis of tumor cells, including SNAIL, SLUG, ZEB1 and ZEB2 [33, 34]. Among them, ZEB1 (characterized by the presence of 2 zinc finger clusters) is a well investigated transcriptional factor to act as a driver of EMT and cancer progression toward metastasis and invasion [35]. In our study, we have recognized ZEB1 as a downstream protein of PIK3R3 by evaluating the correlation between above-mentioned transcriptional factors and PIK3R3 expression based on the data obtained from TCGA, and assessing their expression in stable PIK3R3 overexpression and knockdown cells.…”

The gain‐of‐function mutation E76K in SHP2 promotes CAC tumorigenesis and induces EMT via the Wnt/β‐catenin signaling pathway

“…ZEB1 is an inducer of EMT. Zhang et al suggested that the regulation of ZEB1 by SHP2 is critical for PDGFA/PDGFRα signaling in the driving of EMT, cell migration, and invasion in glioma . In contrast, when we knocked down β‐catenin with siRNAs, EMT was reversed, and the migration of CRC cells was inhibited.…”