title: Transgenic disruption of gap junctional intercellular communication enhances early but not late stage hepatocarcinogenesis in the rat.
abstract: Much experimental evidence supports the conclusion that loss of gap junctional intercellular communication (GJIC) contributes to carcinogenesis. Transgenic rats featuring a dominant negative mutant of the connexin 32 gene under albumin promoter control (Cx32Delta Tg-High and Cx32Delta Tg-Low lines, respectively with high and low copy numbers of the transgene) have disrupted GJIC, as demonstrated by scrape dye-transfer assay in vivo as previous report by Asamoto et al. (2004). In the present study, we investigated the susceptibility of these transgenic rats to a single intraperitoneal administration of diethylnitrosamine (DEN), and found a significant increase in preneoplastic glutathione S-transferase placental form (GST-P) positive lesions in the livers of Cx32Delta Tg-High but not Cx32Delta Tg-Low rats. However, incidences of adenomas and hepatocellular carcinomas were not elevated at the end of the experiment (52 weeks). In addition, we investigated the promotional effect of phenobarbital (PB) on Cx32Delta Tg-High rats pretreated with DEN and found enhanced formation of GST-P positive lesions, in contrast to the lack of promoting effects reported for Cx32 deficient mice. The results indicate that although both high and low expression of the dominant negative connexin 32 mutant gene in our rats is able to inhibit gap junctional capacity, only high expression is effective at enhancing susceptibility to early stage DEN-induced liver carcinogenesis.
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hokaiwado
authors.forename: Makoto
authors.initials: M
authors.lastname: Asamoto
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
mesh_terms: D000477:Alkylating Agents; D000818:Animals; D030801:Animals, Genetically Modified; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics*; D003043:Cocarcinogenesis; D017630:Connexins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004052:Diethylnitrosamine; D004198:Disease Susceptibility; D004790:Enzyme Induction; D017629:Gap Junctions / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006498:Hepatectomy; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D009154:Mutation; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D051381:Rats; D013997:Time Factors; D000097002:Gap Junction beta-1 Protein
chemical_list: D000477:Alkylating Agents; D017630:Connexins; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D010634:Phenobarbital; D000097002:Gap Junction beta-1 Protein