Abstract
Increased hepatic expression of the Forkhead transcription factor FoxM1B in adult mice accelerates hepatocyte proliferation after partial hepatectomy, while in hepatocytes in intact liver the transgenic (Tg) protein is inactive and has no effect on proliferation. To investigate the influence of FoxM1B on liver tumor formation, we examined the effect of sustained enrichment of FoxM1B in the hepatocytes of mice treated with a diethylnitrosamine (DEN)/phenobarbital tumor induction protocol. Tg enrichment of FoxM1B in hepatocytes did not increase the proliferation rate in normal liver tissue even when the protein was localized to the nucleus. However, it did cause an increase in the proliferation rate and size of preneoplastic and early neoplastic lesions, although having no effects on the total numbers of these lesions. As tumors progressed to hepatocellular carcinomas, the additional Tg FoxM1B protein had no effect on cell proliferation, and there was no increase in tumor burden compared to wild-type animals. This suggests that the artificial enrichment of FoxM1B in the liver, which has been suggested as a gene therapy protocol for liver dysfunction with aging, may not be tumorigenic in that organ.
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Acknowledgements
We thank William Chen, Vladimir Kalinichenko and Pradip Raychaudhuri for their comments on an earlier version of this manuscript and David Lazkinski for comments on this version. We thank Matthew Wettergreen for his help with the initial stages of this project, John Hunniford for genotyping, Xinhe Wang for her advice on immunohistochemistry and the gift of the cloned murine FoxM1B genomic DNA and Vladimir Kalinichenko, William Chen and Thomas Lakous for their advice on immunohistochemistry. We thank members of the Costa laboratory for sharing equipment with us. This work was supported by US Public Health Service Grant Ro1 CA 85529-05 from NCI (GRA) and RO1 DK 54687-05 from NIDDK (RHC).
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Kalinina, O., Kalinin, S., Polack, E. et al. Sustained hepatic expression of FoxM1B in transgenic mice has minimal effects on hepatocellular carcinoma development but increases cell proliferation rates in preneoplastic and early neoplastic lesions. Oncogene 22, 6266–6276 (2003). https://doi.org/10.1038/sj.onc.1206640
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DOI: https://doi.org/10.1038/sj.onc.1206640
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