Diethylnitrosamine induces long-lasting re-expression of insulin-like growth factor II during early stages of liver carcinogenesis in mice.
The expression of the insulin-like growth factor II (IGF-II) gene (Igf2) in rodents is completely abrogated in almost all adult tissues. A prominent exception are neoplasms in which IGF-II frequently serves as an autocrine growth factor. We have investigated the potential role of Igf2 expression during liver carcinogenesis. After application of diethylnitrosamine (DEN) preneoplastic foci and adenomas emerged in liver tissue of wild-type and phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II transgenic mice. Surprisingly, number and size of preneoplastic foci were not significantly increased in PEPCK-IGF-II mice as compared with wild-type animals. In situ preparation showed that early adenomas expressed Igf2 transcripts. Reverse transcriptase polymerase chain reaction (RT-PCR) and restriction enzyme analysis confirmed that DEN treatment had indeed reactivated the hepatic expression of murine Igf2 in control mice in a dose-dependent manner. This re-expression of Igf2 persisted for at least 18 months. Species-specific RT-PCR analyses also revealed the presence of murine Igf2 mRNAs in some PEPCK-IGF-II mice. A similar reactivation of Igf2 was detected in bovine growth hormone transgenic mice which develop hepatocellular neoplasms with high frequency. Our results suggest that reactivation of Igf2 is an early event during hepatocarcinogenesis in mice. Its appearance in two independent animal models suggests that Igf2 may be important at pivotal checkpoints of hepatocarcinogenesis.
Lahm
Harald
H
Institute of Molecular Animal Breeding, Gene Center, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany. harald.lahm@thoraxklinik-heidelberg.de
Gittner
Katinka
K
Krebs
Ottheinz
O
Sprague
Lisa
L
Deml
Erhard
E
Oesterle
Doris
D
Hoeflich
Andreas
A
Wanke
Rüdiger
R
Wolf
Eckhard
E
D000236:Adenoma / Q000378:metabolism; D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D004052:Diethylnitrosamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
D000477:Alkylating Agents; D004052:Diethylnitrosamine; D012313:RNA; D007335:Insulin-Like Growth Factor II; D010729:Phosphoenolpyruvate Carboxykinase (GTP)