Persistent and remodeling hepatic preneoplastic lesions present differences in cell proliferation and apoptosis, as well as in p53, Bcl-2 and NF-kappaB pathways.
During rat hepatocarcinogenesis preneoplastic lesions (PNL) emerge which may persist (pPNL) and be sites of progress to cancer or suffer remodeling (rPNL) tending to disappear. Cellular and molecular mechanisms involved in both phenotypes are not sufficiently elucidated. pPNL and rPNL cellular proliferation and apoptosis were evaluated in rats submitted to the resistant hepatocyte (RH) model, and an adjusted growth index (AGI) was established. p53, Bcl-2, and NF-kappaB p65 subunit expression was evaluated by immunohistochemistry in pPNL and rPNL. p65 expression and NF-kappaB activation was evaluated by Western blot assays in whole livers. A lower number of BrdU-stained hepatocyte nuclei/mm(2) and higher number of apoptotic bodies (AB) per mm(2) were observed in remodeling compared to pPNL. Cytoplasmic p53 accumulation is related to increased hepatocarcinoma malignancy. We observed that 71.3% pPNL and 25.4% rPNL (P < 0.05) presented p53 staining in the cytoplasm. Similarly, 67.7% pPNL and 23.1 % rPNL (P < 0.05) presented increased Bcl-2 staining. Thirty-two percent pPNL and 15.6% rPNL (P < 0.05) presented p65 staining. Compared to normal rats, increase (P < 0.05) of hepatic p65 expression and NF-kappaB activation in rats submitted to the RH model was observed. In agreement to previous studies hepatic pPNL and rPNL differ regarding cell proliferation and apoptosis. Moreover, persistence and remodeling involve differences in p53, Bcl-2, and NF-kappaB pathways. These data point to molecular pathways that may direct preneoplastic lesions to spontaneously regress or to progress to cancer. J. Cell. Biochem. 103: 538-546, 2008. (c) 2007 Wiley-Liss, Inc.
Mazzantini
Rogério Pietro
RP
Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
de Conti
Aline
A
Moreno
Fernando Salvador
FS
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury; D003043:Cocarcinogenesis; D004261:DNA Replication; D004052:Diethylnitrosamine / Q000633:toxicity; D018450:Disease Progression; D005786:Gene Expression Regulation; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D051996:Transcription Factor RelA / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene