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Oncotarget: The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma


Here is a link to a video interview with Dr. Pfeffer about this research on the Oncotarget YouTube Channel

Oncotarget published “The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma” which reported that in GICs, STAT3 not only promoted pro-tumorigenic genes involved in cell cycle progression, remodeling of the extracellular matrix, as well as genes encoding cytokines and growth factors, but also suppressed IFN response genes.

Moreover, while some of the genes were dependent on Y705-STAT3 phosphorylation, other genes were independent of Y705-STAT3 phosphorylation.

Dr. Lawrence M. Pfeffer from the Department of Pathology and Laboratory Medicine, and Center for Cancer Research at the University of Tennessee Health Science Center in Memphis, TN, said "By targeted arrays and RNA-sequence analysis, we found STAT3 regulated genes in GICs that are important in various pro-tumorigenic pathways."

STAT3 contains a DNA binding domain and a C-terminal transactivation domain which undergoes both Tyrosine 705 and Serine 727 phosphorylation, which regulate STAT3 activity.

Previously, the researchers reported that STAT3 undergoes constitutive Y705 phosphorylation in GICs isolated from several GBM patient-derived xenograft models.

In addition, they also found that a STAT3 inhibitor prevented STAT3 Y705 phosphorylation and attenuated GIC-driven tumor growth.

Figure 9: Identification of downstream effectors of STAT3 in GBM tumor specimens. The expression of STAT3 and its targeted genes identified in the GBMX16 GICs by RNA-seq was examined in 528 GBM specimens included in the TCGA database. (A) Expression levels of STAT3 mRNA in GBM tumors and adjacent normal tissues. (B) Survival curves of GBM with high or low expression of STAT3. (C) Correlation between STAT3 expression and averaged expression level of STAT3-activated genes in GBM as listed in the inserted table. (D) Survival curves of GBM with high or low expression of STAT3-activated genes. (E) Outcome parameters from correlation analysis of the expression levels of STAT3-target genes and STAT3, and outcome parameters from survival curve comparison of GBM with high (top 25%) and low (bottom 25%) expression of STAT3 or its target genes.

In order to study STAT3 function, they developed a Doxycycline-inducible STAT3 knockdown system in GICs to determine whether the STAT3 Y705 and S727 phosphorylation sites play distinct roles in regulating GIC function in vitro and in vivo.

They found that STAT3 is critical for GBM tumorigenesis and that the Y705 phosphorylation site is indispensable for GIC tumor growth.

The Pfeffer research team concluded in their Oncotarget Research Paper, "Since STAT3 is an important oncogenic driver of GBM, the identification of these STAT3 regulated pathways in GICs will inform the development of better targeted therapies against STAT3 in GBM and other cancers."

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DOI - https://doi.org/10.18632/oncotarget.25188

Full text - https://www.oncotarget.com/article/25188/text/

Correspondence to - Lawrence M. Pfeffer - lpfeffer@uthsc.edu

Keywords - STAT3, glioblastoma, phosphorylation, gene expression, tumorigenesis

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