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Segnali di proliferazione e apoptosi sono sotto controllo genetico durante la cancerogenesi epatica di ratto

Sini, Marcella (2009) Segnali di proliferazione e apoptosi sono sotto controllo genetico durante la cancerogenesi epatica di ratto. Doctoral Thesis.

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Abstract

Fast growth and deregulation of G1 and S phases characterizes preneoplastic and neoplastic liver lesions of genetically susceptible F344 rats, whereas a G1-S block in lesions of resistant BN rats explains their low progression capacity. We comparatively investigated the role of Ras/Erk pathway inhibitors, involved in growth restraint and cell death, in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis. Moderate activation of Ras, Raf-1 and Mek proteins was paralleled in both rat models by strong induction of Dab2 and Rkip inhibitors. Levels of Dusp1, a specific ERK inhibitor, increased only in BN rat lesions, leading to modest ERK activation, whereas a progressive Dusp1 decline occurred in corresponding lesions from F344 rats and was accompanied by elevated ERK activation. Furthermore, a gradual increase of Rassf1A/Nore1A/Mst1-driven apoptosis was detected in both rat strains, with highest levels in BN hepatocellular carcinoma (HCC), whereas loss of Dab2IP, a protein implicated in ASK1- dependent cell death, occurred only in F344 rat HCC, resulting in significantly higher apoptosis in BN than F344 HCC. Our results indicate a control of the Ras/Erk pathway and the pro-apoptotic Rassf1A/Nore1A and Dab2IP/Ask1 pathways by HCC susceptibility genes. Dusp1 possesses a prominent role in the acquisition of the phenotype resistant to HCC by BN rats, whereas late activation of RassF1A/Nore1A and Dab2IP/Ask1 axes is implicated in the highest apoptosis characteristic of BN HCC.

Item Type:Doctoral Thesis
ID Code:791
Publisher:Universita' degli studi di Sassari
Uncontrolled Keywords:Carcinoma epatocellulare, DUSP1, ERK, RASSF1A/NORE1A, trasduzione del segnale
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Cicli, scuole e corsi:Ciclo 21 > Corsi > Epidemiologia molecolare dei tumori
Deposited On:18 Aug 2009 10:03

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