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- Title
Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control.
- Authors
Calvisi, Diego F.; Pinna, Federico; Pellegrino, Rossella; Sanna, Valeria; Sini, Marcella; Daino, Lucia; Simile, Maria M.; De Miglio, Maria R.; Frau, Maddalena; Tomasi, Maria L.; Seddaiu, Maria A.; Muroni, Maria R.; Feo, Francesco; Pascale, Rosa M.
- 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. © 2008 Wiley-Liss, Inc.
- Publication
International Journal of Cancer, 2008, Vol 123, Issue 9, p2057
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.23720