Visco, Elena (2015) Ruolo oncogeno della subunità catalitica p110 della fosfoinositide-3-cinasi (PI3KCA) durante la progressione del carcinoma epatocellulare in modelli sperimentali murini e la sua importanza terapeutica. Doctoral Thesis.
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Aim: Phosphatidylinositol4,5-bisphosphate3-kinase catalytic subunit alpha isoform (PI3KCA), is considered an important oncogene implicated in the development of a wide variety of human cancers. PIK3CA oncogene catalyzes the production of phosphatidylinositol-3,4,5triphosphate (PIP3). PIP3 activates downstream signaling components such as AKT protein kinase and promotes cell growth and survival. PI3KCA mutations lead to constitutive activation of p110 alpha enzymatic activity, stimulate AKT signaling, and allow growth factor-independence. Previous observation showed an AKT activation, after hydrodynamic myr-AKT gene delivery.
Methods: In my project we evaluated the development of liver cancer in PI3KCA mutant (E545K) overexpressing mice. PI3KCA mutants were obtained by PI3KCA mutant gene delivered through hydrodynamic injection in 129/Sv-C57BL/6 mice. Microarray analysis was performed, and it has been evaluated the gene expression profiles of liver lesions developed in PIK3CA-E545K mice in order to identify PI3KCA gene targets and signal transduction pathways involved in hepatocellular carcinoma (HCC) development and progression.
Results: Overexpression of PIK3CA-E545K resulted in the development of multiple liver tumors in 129/Sv-C57BL/6 mice after 6 months of latency. cDNA microarray technology showed the overexpression of a group of genes involved in lipid metabolism, cell proliferation and survival in the lesions of PIK3CA-E545 mice when compared with control mice.
Conclusions: The present results indicate that oncogenic forms of PIK3CA are sufficient to induce malignant tansformation of the mouse liver. We have also identified a number of PIK3CA targets, whose investigation might be helpful both for a better understanding of the molecular pathogenesis of HCC and the development of new therapeutic strategies against this deadly disease.
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