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Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control

Calvisi, Diego Francesco and Pinna, Federico and Pellegrino, Rossella and Sanna, Vanna Annunziata and Sini, Marcella and Daino, Lucia and Simile, Maria Maddalena and De Miglio, Maria Rosaria and Frau, Maddalena and Tomasi, Maria Lauda and Seddaiu, Maria Antonietta and Muroni, Maria Rosaria and Feo, Francesco and Pascale, Rosa Maria (2008) Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control. International Journal of Cancer, Vol. 123 (9), p. 2057-2064. eISSN 1097-0215. Article.

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DOI: 10.1002/ijc.23720

Abstract

Fast growth and deregulation of G1 and S phases characterize 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. However, signal transduction pathways responsible for the different propensity of lesions from the 2 rat strains to evolve to malignancy remain unknown. Here, 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. Taken together, 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:Article
ID Code:1778
Status:Published
Refereed:Yes
Uncontrolled Keywords:Hepatocellular carcinoma, Dusp1, Erk, RassF1A/ Nore1A, signal transduction, genetic predisposition
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Wiley-Liss
eISSN:1097-0215
Additional Information:Pubblicato online l'11 agosto 2008.
Deposited On:18 Aug 2009 10:06

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