Sanna, Valeria (2009) Studio della regolazione genetica della via di trasduzione del segnale iNOS dipendente nell'epatocarcinoma sperimentale e umano. Doctoral Thesis.
Mounting evidence underlines the role of inducible nitric oxide synthase (iNOS) in hepatocellular carcinoma (HCC) development,but its functional interactions with pathways involved in HCC progression remain uninvestigated. We analyzed in preneoplastic and neoplastic livers from Fisher 344 and Brown Norway rats, possessing different genetic predisposition to HCC and in human HCC iNOS function and interactions with nuclear factor-kB (NF-kB) and Ha-RAS/extracellular signal-regulated kinase (ERK) during hepatocarcinogenesis; influence of genetic predisposition to liver cancer on these pathways. We found progressive iNos induction in rat at higher levels in the most aggressive rats. iNOS, inhibitor of kB kinase/NF-kB and RAS/ERK upregulation was significantly higher in HCC with poorer prognosis, positively correlated with tumor proliferation, genomic instability and microvascularization and negatively with apoptosis. Suppression of iNOS signaling led to decreased HCC growth and NF-kB and RAS/ERK expression and increased apoptosis both in vivo and in vitro. Conversely, block of NF-kB signaling or ERK signaling caused iNOS downregulation in HCC cell lines. These findings indicate that iNOS cross talk with NFkB and Ha-RAS/ERK cascades influences HCC growth and prognosis, suggesting that key component of iNOS signaling could represent important therapeutic targets for human HCC.
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