title: Crosstalk between PTEN/Akt2 and TGFbeta signaling involving EGF receptor down-regulation during the tumor promotion process from the early stage in a rat two-stage hepatocarcinogenesis model.
abstract: The present study investigated the involvement of signaling of phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/protein kinase B (Akt) and transforming growth factor-beta (TGFbeta) as well as receptor tyrosine kinases in the tumor promotion processes in a two-stage hepatocarcinogenesis model using male F344 rats. The cellular localization of related molecules was examined in liver cell foci expressing glutathione S-transferase placental form (GST-P) at the early stage of tumor promotion by fenbendazole (FB), piperonyl butoxide, or thioacetamide. Distribution in the liver cell foci and neoplastic lesions positive for GST-P was also examined at the later stage of FB promotion. In contrast to the initiation-alone cases, subpopulations of GST-P-positive foci induced by promotion for 6 weeks, regardless of the promoting chemicals used, enhanced down-regulation of PTEN and up-regulation of phosphorylated (active) Akt2 and phosphorylated substrate(s) of Akt-kinase activity. Also, up-regulation of TGFbeta receptor I and down-regulation of epidermal growth factor receptor (EGFR) were enhanced in the subpopulation of GST-P-positive foci in all promoted cases. A similar pattern of cellular distribution of these molecules was also observed in the neoplastic lesions at the late stage. These results suggest a crosstalk between Akt2 and TGFbeta signaling that involves a mechanism requiring EGFR down-regulation during the entire tumor promotion process starting from the early stage. In particular, a shift in subcellular localization of phosphorylated substrate(s) of Akt from the cell membrane in liver cell foci to the cytoplasm in carcinomas was observed, suggesting an alteration of the function or activity of the corresponding molecule(s).
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Taniai
authors.forename: Masaomi
authors.initials: M
authors.lastname: Kawai
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Dewa
authors.forename: Jihei
authors.initials: J
authors.lastname: Nishimura
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Harada
authors.forename: Yukie
authors.initials: Y
authors.lastname: Saegusa
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D010455:Peptides; D016212:Transforming Growth Factor beta; D066246:ErbB Receptors; C494923:Akt2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat