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SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans
Kun-Wei Liu, … , Bo Hu, Shi-Yuan Cheng
Kun-Wei Liu, … , Bo Hu, Shi-Yuan Cheng
Published February 14, 2011
Citation Information: J Clin Invest. 2011;121(3):905-917. https://doi.org/10.1172/JCI43690.
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Research Article Oncology

SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans

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Abstract

Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor α (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFRα conferred tumorigenicity to Ink4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFRα-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFRα, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFRα and PDGF-A are co-expressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas.

Authors

Kun-Wei Liu, Haizhong Feng, Robert Bachoo, Andrius Kazlauskas, Erin M. Smith, Karen Symes, Ronald L. Hamilton, Motoo Nagane, Ryo Nishikawa, Bo Hu, Shi-Yuan Cheng

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Figure 3

PDGF-A overexpression enhances tumorigenesis of INK4A/ARF-deficient but not WT INK4A/ARF human glioma cells.

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PDGF-A overexpression enhances tumorigenesis of INK4A/ARF-deficient but ...
(A) RT-PCR (top) and IB analyses (bottom) of INK4A/ARF-deficient LN444 and LN443 and WT INK4A/ARF LN-Z308 and LN319 human glioma cells. (B) IB analysis of PDGF-A overexpression in glioma cells with endogenous PDGFRα expression. PDGFRα was phosphorylated at tyrosine residues in PDGF-A–expressing cells, but not in parental cells that have no detectable PDGF-A. P, parental cells; A, PDGF-A–overexpressing cells. β-Actin was used as a loading control in both A and B. (C) Representative images (left) and quantification (right) of anchorage-independent growth of various glioma cells in soft agar. Scale bars: 1 mm. Data are presented as percentage of the respective parental cells (mean ± SD). *P < 0.001, Student’s t test. (D–K) Representative H&E-stained images of various brain sections from 2 independent experiments with 3–5 mice per group with similar results. Brains were harvested 50–55 days (D and H), 75–80 days (E and I), and 45–50 days (F, G, J, and K) after transplantation. Arrows indicate gliomas formed in the brain. Scale bar: 1 mm.
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