Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control.
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.
Calvisi
Diego F
DF
Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
Pinna
Federico
F
Pellegrino
Rossella
R
Sanna
Valeria
V
Sini
Marcella
M
Daino
Lucia
L
Simile
Maria M
MM
De Miglio
Maria R
MR
Frau
Maddalena
M
Tomasi
Maria L
ML
Seddaiu
Maria A
MA
Muroni
Maria R
MR
Feo
Francesco
F
Pascale
Rosa M
RM
D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D054638:Dual Specificity Phosphatase 1 / Q000032:analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology; D011230:Precancerous Conditions / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D048049:Extracellular Signal-Regulated MAP Kinases; D048848:MAP Kinase Kinase Kinase 5; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D018631:ras Proteins