Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. The aberrant activation of STAT3 commonly occurs in GBM and is a key player in GBM tumorigenesis. Yet, the aberrant activation of STAT3 signaling is not fully understood. Here, we report that SH2B adaptor protein 3 (SH2B3) is highly expressed in GBM and preferentially expressed in GBM stem cells (GSCs). Moreover, SH2B3 high expression predicts worse survival of GBM patients. Targeting SH2B3 considerably impairs GBM cell proliferation, migration, and GSCs’ self-renewal in vitro as well as xenograft tumors growth in vivo. Additionally, we provide evidence suggesting that STAT1 directly binds to the promoter of SH2B3 and activates SH2B3 expression in the transcriptional level. Functionally, SH2B3 facilitates GBM progression via physically interacting with gp130 and acting as an adaptor protein to transduce IL-6/gp130/STAT3 signaling. Together, our work firstly uncovers that the STAT1/SH2B3/gp130/STAT3 signaling axis plays critical roles in promoting GBM progression and provides insight into new prognosis marker and therapeutic target in GBM.

The mortality rate of patients with glioma is increasing worldwide per annum. This is attributed to the poor disease prognosis, most notably for high-grade gliomas (grade III and IV), which does not improve the overall patient survival. The dysregulation of microRNA (miRNA/miR)-124-3p is found in a variety of tumors. However, the association between miR-124-3p expression and its target genes in glioma has not been thoroughly elucidated. The present study aimed to explore the possible effects of miR-124-3p and its proved target, Ras homology Growth-related (RhoG), on the oncogenic events associated with glioblastoma multiforme (GBM) development. The data demonstrated an inverse association between miR-124-3p and RhoG expression levels during GBM progression in GBM tissues and cells. U87 and U251 cells were employed for the in vitro assays. Luciferase reporter assays revealed that miR-124-3p interacted with RhoG at the RhoG 3' untranslated region and inhibited RhoG expression in GBM cells. Functionally, enriched miR-124-3p repressed RhoG transcription and suppressed GBM cell proliferation and migration, promoting apoptosis and altering the expression or activity of the apoptosis-related proteins of GBM cells. By contrast, the inhibition of miR-124-3p in GBM cells upregulated RhoG levels and promoted the proliferation of GBM cells. The knock down of RhoG expression by specific small interfering RNA sequences partially neutralized the effects induced by the miR-124-3p inhibitor. In conclusion, the present study demonstrated the crucial effects of miR-124-3p on the development and deterioration of GBM by targeting RhoG.

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.