Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model

Journal Article · Sun Aug 01 04:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.04.016· OSTI ID:21451177

Ichimura, Ryohei ^[1]; Mizukami, Sayaka ^[1]; Takahashi, Miwa ^[2]; Taniai, Eriko ^[1]; Kemmochi, Sayaka ^[1]; Mitsumori, Kunitoshi ^[1]; Shibutani, Makoto ^[1]

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1. Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)
2. Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)

To clarify the involvement of signaling of transforming growth factor (TGF)-{beta} during the hepatocarcinogenesis, the immunohistochemical distribution of related molecules was analyzed in relation with liver cell lesions expressing glutathione S-transferase placental form (GST-P) during liver tumor promotion by fenbendazole, phenobarbital, piperonyl butoxide, or thioacetamide, using rats. Our study focused on early-stage promotion (6 weeks after starting promotion) and late-stage promotion (57 weeks after starting promotion). With regard to Smad-dependent signaling, cytoplasmic accumulation of phosphorylated Smad (phospho-Smad)-2/3 - identified as Smad3 by later immunoblot analysis - increased in the subpopulation of GST-P{sup +} foci, while Smad4, a nuclear transporter of Smad2/3, decreased during early-stage promotion. By late-stage promotion, GST-P{sup +} lesions lacking phospho-Smad2/3 had increased in accordance with lesion development from foci to carcinomas, while Smad4 largely disappeared in most proliferative lesions. With regard to Smad-independent mitogen-activated protein kinases, GST-P{sup +} foci that co-expressed phospho-p38 mitogen-activated protein kinase increased during early-stage promotion; however, p38-downstream phospho-activating transcriptional factor (ATF)-2, ATF3, and phospho-c-Myc, were inversely downregulated without relation to promotion. By late-stage promotion, proliferative lesions downregulated phospho-ATF2 and phospho-c-Myc along with lesion development, as with downregulation of phospho-p38 in all lesions. These results suggest that from the early stages, carcinogenic processes were facilitated by disruption of tumor suppressor functions of Smad-dependent signaling, while Smad-independent activation of p38 was an early-stage phenomenon. GST-P{sup -} foci induced by promotion with agonists of peroxisome proliferator-activated receptor-{alpha} did not change Smad expression, suggesting an aberration in the Smad-dependent signaling prerequisites for induction of GST-P{sup +} proliferative lesions.

• OSTI ID: 21451177
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 246; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANESTHETICS
ANIMAL CELLS
ANIMALS
ANTICONVULSANTS
AZINES
BARBITURATES
BODY
CARCINOMAS
CENTRAL NERVOUS SYSTEM AGENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DIGESTIVE SYSTEM
DISEASES
DRUGS
ENZYMES
GLANDS
GLUTATHIONE
GROWTH FACTORS
HETEROCYCLIC COMPOUNDS
HYPNOTICS AND SEDATIVES
LIVER
LIVER CELLS
MAMMALS
MITOGENS
NEOPLASMS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PEPTIDES
PHENOBARBITAL
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
POLYPEPTIDES
PROTEINS
PYRIMIDINES
RADIOPROTECTIVE SUBSTANCES
RATS
RESPONSE MODIFYING FACTORS
RODENTS
SOMATIC CELLS
TRANSFERASES
VERTEBRATES