| Autor: |
Rahrmann, Eric P., Moriarity, Branden S., Otto, George M., Watson, Adrienne L., Choi, Kwangmin, Collins, Margaret H., Wallace, Margaret, Webber, Beau R., Forster, Colleen L., Rizzardi, Anthony E., Schmechel, Stephen C., Ratner, Nancy, Largaespada, David A. |
| Zdroj: |
American Journal of Pathology; July 2014, Vol. 184 Issue: 7 p2082-2098, 17p |
| Abstrakt: |
Malignant peripheral nerve sheath tumors (MPNSTs) are genetically diverse, aggressive sarcomas that occur sporadically or in association with neurofibromatosis type 1 syndrome. Reduced TP53gene expression and amplification/overexpression of the epidermal growth factor receptor (EGFR) gene occur in MPNST formation. We focused on determining the cooperativity between reduced TP53expression and EGFRoverexpression for Schwann cell transformation in vitro(immortalized human Schwann cells) and MPNST formation in vivo(transgenic mice). Human gene copy number alteration data, microarray expression data, and TMA analysis indicate that TP53haploinsufficiency and increased EGFRexpression co-occur in human MPNST samples. Concurrent modulation of EGFRand TP53expression in HSC1λ cells significantly increased proliferation and anchorage-independent growth in vitro. Transgenic mice heterozygous for a Trp53-null allele and overexpressing EGFRin Schwann cells had a significant increase in neurofibroma and grade 3 PNST (MPNST) formation compared with single transgenic controls. Histological analysis of tumors identified a significant increase in pAkt expression in grade 3 PNSTs compared with neurofibromas. Array comparative genome hybridization analysis of grade 3 PNSTs identified recurrent focal regions of chromosomal gains with significant enrichment in genes involved in extracellular signal–regulated kinase 5 signaling. Collectively, altered p53expression cooperates with overexpression of EGFRin Schwann cells to enhance in vitrooncogenic properties and tumorigenesis and progression in vivo. |
| Databáze: |
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