Signaling Networks Associated with AKT Activation in Non-Small Cell Lung Cancer NSCLC: New Insights on the Role of Phosphatydil-Inositol-3 kinaseReportar como inadecuado




Signaling Networks Associated with AKT Activation in Non-Small Cell Lung Cancer NSCLC: New Insights on the Role of Phosphatydil-Inositol-3 kinase - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Aberrant activation of PI3K-AKT signalling represents one of the most common molecular alterations in lung cancer, though the relative contribution of the single components of the cascade to the NSCLC development is still poorly defined. In this manuscript we have investigated the relationship between expression and genetic alterations of the components of the PI3K-AKT pathway KRAS, the catalytic subunit of PI3K p110α, PTEN, AKT1 and AKT2 and the activation of AKT in 107 surgically resected NSCLCs and have analyzed the existing relationships with clinico-pathologic features. Expression analysis was performed by immunohistochemistry on Tissue Micro Arrays TMA; mutation analysis was performed by DNA sequencing; copy number variation was determined by FISH. We report that activation of PI3K-AKT pathway in Italian NSCLC patients is associated with high grade G3–G4 compared with G1–G2; n = 83; p<0.05 and more advanced disease TNM stage III vs. stages I and II; n = 26; p<0.05. In addition, we found that PTEN loss 41-104, 39% and the overexpression of p110α 27-92, 29% represent the most frequent aberration observed in NSCLCs. Less frequent molecular lesions comprised the overexpression of AKT2 18-83, 22% or AKT1 17-96, 18%, and KRAS mutation 7-63, 11%. Our results indicate that, among all genes, only p110α overexpression was significantly associated to AKT activation in NSCLCs p = 0.02. Manipulation of p110α expression in lung cancer cells carrying an active PI3K allele NCI-H460 efficiently reduced proliferation of NSCLC cells in vitro and tumour growth in vivo. Finally, RNA profiling of lung epithelial cells BEAS-2B expressing a mutant allele of PIK3 E545K identified a network of transcription factors such as MYC, FOS and HMGA1, not previously recognised to be associated with aberrant PI3K signalling in lung cancer.



Autor: Marianna Scrima, Carmela De Marco, Fernanda Fabiani, Renato Franco, Giuseppe Pirozzi, Gaetano Rocco, Maria Ravo, Alessandro Weisz

Fuente: http://plos.srce.hr/



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