This CTRP8-RXFP1-STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM.
Given the role of the tumor microenvironment as a regulator of STAT3 activity, we tested the effect of the STAT3 inhibitor SH-4-54 on GBM migration and survival.
Western blot analysis revealed elevated SHP-1 expression and reduced phosphorylated (p)-STAT3 expression in glioblastoma cells treated with VB compared with controls.
Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM.
RESULTS The analyses revealed a prominent role for STAT3 in the mesenchymal but not in other GBM subtypes, which can be reliably used to classify patients with mesenchymal GBM into 2 groups according to phosphorylated STAT3 expression level.
Here, we found that miR-124 expression was downregulated in GBM tissues and U87 and U251 cells (all p < 0.001) but not associated with blood routine (RBC, WBC count, etc.) and liver and renal function indicators (all p > 0.05).By contrast, STAT3 was upregulated.
The importance of signal transducer and activator of transcription 3 (STAT3) signaling in the growth and survival of glioblastoma cells has been well documented, while the reasons leading to STAT3 activation remains to be elucidated.
Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3.
These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.
In clinical samples of GBMs, high ALK expression without gene rearrangements or mutations was frequently observed in perivascular lesions, in contrast to the relatively low expression in the perinecrotic areas, which was positively correlated with N-myc and phosphorylated (p) Stat3 scores and Ki-67 labeling indices.
The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model.
Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in glioblastoma and has been identified as a relevant therapeutic target in this disease and many other human cancers.
15α-MP treatment induced loss of viability of breast cancer (MDA-MB-231, MDA-MB-468) and glioblastoma (U251MG) lines and glioblastoma patient-derived xenograft cells (G22) that harbor aberrantly active Stat3, with only moderate or little effect on the human breast cancer, MCF7, colorectal adenocarcinoma Caco-2, normal human lung fibroblast, WI-38, or normal mouse embryonic fibroblast (MEF Stat3<sup>fl/fl</sup>) lines that do not harbor constitutively active Stat3 or the Stat3-null (Stat3<sup>-/-</sup>) mouse astrocytes.
Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic.
Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis.
Collectively, our study identifies a novel translational and targetable role for BIRC3 expression as a predictor of aggressiveness and therapeutic resistance to TMZ and RT mediated by STAT3 and PI3K signaling in GBM.