Platelet-derived growth factor receptor alpha overexpression cooperates with ink4a/arf loss to promote gliomagenesis---roles of shp-2 and pi3k pathways

摘要: BACKGROUND: Human gliomas account for the most common and malignant tumors in central nervous system (CNS). Despite optimal treatments, survival of patients with high-grade glioblastoma multiforme (GBM) remains poor. Recent coordinated genomic analyses a large cohort clinical GBM specimens identified frequent co-alterations genes three core pathways—the P53, retinoblastoma (RB), receptor tyrosine kinase (RTK) pathways that are crucial gliomagenesis. Further multi-institutional efforts have sub-classified GBMs into four relevant subtypes based on their signature genetic lesions. Among them, PDGFRA overexpression is concomitant loss CDKN2A locus (encoding P16INK4A P14ARF) number within one subtype GBMs. To better understand design therapeutic strategies against driven by abnormal platelet-derived growth factor (PDGF) signaling, functional studies using human or mouse models needed. MAJOR FINDINGS: In order to establish model allows us assess contributions different signaling PDGFRα-induced glioma formation, we generated Ink4a/Arf-deficient primary astrocytes (referred as mAst hereafter) cells overexpress PDGFRα and/or PDGF-A. We found activation confers tumorigenicity brain. Restoration p16INK4a but not p19ARF retroviral transduction suppresses PDGFRα-promoted formation. Mechanistically, abrogation modules lost capacity bind SH-2-containing phosphotyrosine phosphatase SHP-2 Phosphoinositol 3'-Kinase (PI3K) significantly diminished tumorigenesis. Furthermore, inhibition shRNAs pharmacological inhibitors disrupted interaction PI3K PDGFRα, suppressed downstream AKT/mTOR activation, impaired tumorigenesis Ink4a/Arf-null cells, whereas expression an activated mutant rescued effect tumorigenicity. specimens, PDGF-A co-expressed such co-expression linked SHP-2/AKT/mTOR-signaling. Our data thus suggest glioblastomas Ink4a/Arf deficiency, overexpressed promotes through PI3K/AKT/mTOR-mediated pathway regulated activity.SIGNIFICANCE: expect these findings will improve our understanding formation INK4A/ARF aberrations. There were predicted SHP-2/PTPN11 linker interact multiple commonly altered genes. results functionally validate this hypothesis identify converge point several PDGFR, EGFR, PI3K, mTOR frequently deregulated It represents promising target treatments fatal disease.