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 (lgf2) 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 lgf2 expression during liver carcinogenesis. After application of diethylnitrosamine (DEN) preneoplastic foci and adenomas emerged in liver tissue of wildtype 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 lgf2 transcripts. Reverse transcriptase polymerase chain reaction (RT-PCR) and restriction enzyme analysis confirmed that DEN treatment had indeed reactivated the hepatic expression of murine lgf2 in control mice in a dose-dependent manner. This re-expression of lgf2 persisted for at least 18 months. Species-specific RT-PCR analyses also revealed the presence of murine lgf2 mRNAs in some PEPCK-IGF-II mice. A similar reactivation of lgf2 was detected in bovine growth hormone transgenic mice which develop hepatocellular neoplasms with high frequency. Our results suggest that reactivation of lgf2 is an early event during hepatocarcinogenesis in mice. Its appearance in two independent animal models suggests that lgf2 may be important at pivotal checkpoints of hepatocarcinogenesis