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

作者：Ichimura Ryohei; Mizukami Sayaka; Takahashi Miwa; Taniai Eriko; Kemmochi Sayaka; Mitsumori Kunitoshi; Shibutani Makoto^*

来源：Toxicology and Applied Pharmacology, 2010, 246(3): 128-140.

DOI：10.1016/j.taap.2010.04.016

• Rat hepatocarcinogenesis
• Tumor promotion
• Glutathione S-transferase placental form (GST-P)
• Transforming growth factor-beta (TGF beta) signaling
• Smad
• p38 mitogen-activated protein kinase (MAPK)

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(+) foci, while Smad4, a nuclear transporter of Smad2/3, decreased during early-stage promotion By late-stage promotion, GST-P 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(+) 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 downregulanon 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(-) foci induced by promotion with agonists of peroxisome proliferator-activated

• 出版日期2010-8-1