SH3KBP1 Promotes Glioblastoma Tumorigenesis by Activating EGFR Signaling.

Tian Yuan,Jianxiang Lu,Yanpei Wang,Hai Song,Xiangpeng Wang,Chaojia Shi

doi:10.3389/fonc.2020.583984

Abstract

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Overexpression or activation of epidermal growth factor receptor (EGFR) occurs commonly in multiple human cancers and promotes tumorigenesis. However, the underlying molecular mechanism of EGFR aberrant activation and the downstream signaling pathways remains largely unknown. In this study, we report that both SH3-domain kinase binding protein 1 (SH3KBP1) mRNA and protein levels are highly expressed in GBM and its high expression is associated with worse survival of glioma patients. In addition, we provide evidence that SH3KBP1 is prominently expressed in GBM stem cells (GSCs) and have potential to serve as a novel GSCs marker. Moreover, silencing SH3KBP1 dramatically impairs GBM cell proliferation, migration and GSCs self-renewal ability in vitro and xenograft tumors growth in vivo. Most importantly, we found that SH3KBP1 directly interacts with EGFR and may act as an adaptor protein to transduce EGFR signaling. Together, our work uncovers SH3KBP1 as a novel regulator of oncogenic EGFR signaling and also as a potential therapeutic target for GBM patients with EGFR activation.

Highlights

Glioblastoma (GBM, WHO IV glioma) is the most common and lethal tumor of the central nervous system, which accounts for 15.4% of all primary brain tumors and 45.6% of primary malignant brain tumors [1,2,3]
Activation of Epidermal growth factor receptor (EGFR) by binding with ligand or mutation is essential for tumor cell proliferation, migration and cancer stem cell self-renewal
We report a novel function of SH3domain kinase binding protein 1 (SH3KBP1), acting as a new downstream effector of EGFR signaling to mediate EGFRdriven tumorigenesis

Summary

Introduction

Glioblastoma (GBM, WHO IV glioma) is the most common and lethal tumor of the central nervous system, which accounts for 15.4% of all primary brain tumors and 45.6% of primary malignant brain tumors [1,2,3]. Glioma stem cells (GSCs), which are a small subpopulation of cells reside at GBM niches and are characterized by having self-renewal ability and tumorinitiating capacity simultaneously, which have shown to account for GBM initiation, therapeutic resistance and tumor relapse [6,7,8]. New therapies that delete GSCs may be developed by promising initiatives, which are urgently needed for glioma patients’ clinical therapy. A hallmark of human cancers is aberrantly active oncogenic signaling activated by amplified and overexpressed oncogenes [9]. Upon binding to ligands, including EGF or TGF-a, EGFR forms heterodimers or homodimers, leading to its C-terminal tail autophosphorylation and activates downstream signaling through its docking site of SRC homology domain [11].

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