Abstract
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.
Highlights
Glioblastoma (WHO grade IV) is the most common and malignant brain tumor in adults (Brennan et al, 2014)
Short hairpin RNA directly targets human SH2B adaptor protein 3 (SH2B3), or scrambled oligonucleotides were ligated into the pLKO.1 vector
By comparing the expression of SH2B3 in the Glioma-CpG island methylator phenotype (G-CIMP) and non-G-CIMP groups, we found that SH2B3 was highly expressed in the non-G-CIMP group (Figure 1H), which is consistent with the above findings
Summary
Glioblastoma (WHO grade IV) is the most common and malignant brain tumor in adults (Brennan et al, 2014). Glioma stem cells (GSCs) are subpopulation glioma cells that reside at the hierarchical apex, which was considered to account for glioma initiation, malignant progression, therapeutic resistance, and tumor recurrence (Bao et al, 2006a,b; Chen et al, 2012). Strategies to deplete GSCs may be translated into new promising therapies, which are urgently needed. At least 50% of GBM patients who received TMZ treatment eventually develop resistance to TMZ, highlighting an urgent need to understand the molecular mechanism underlying TMZ resistance of GBM. Elaborating the underlying mechanisms of TMZ resistance in GBM patients may provide new insights into GBM patients’ therapy
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