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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

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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References

  • Baudino TA, McKay C, Pendeville-Samain H, Nilsson JA, Maclean KH, White EL, Davis AC, Ihle JN and Cleveland JL . (2002). Genes Dev., 16, 2530–2543.

  • Bell A, Chen Q, DeFrances MC, Michalopoulos GK and Zarnegar R . (1999). Oncogene, 18, 887–895.

  • Birner P, Ritzi M, Musahl C, Knippers R, Gerdes J, Voigtlander T, Budka H and Hainfellner JA . (2001). Am. J. Pathol., 158, 1991–1996.

  • Bosch FX, Ribes J and Borras J . (1999). Semin. Liver Dis., 19, 271–285.

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME (1999) Cell, 96, 857–868.

  • Bucher NL . (1997). Liver Regeneration and Carcinogenesis Jirtle RL (ed). Academic Press: New York.

    Google Scholar 

  • Carlsson P and Mahlapuu M . (2002). Dev. Biol., 250, 1–23.

  • Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, Kadowaki T and Hay N . (2001). Genes Dev., 15, 2203–2208.

  • Costa RH, Kalinichenko VV and Lim L . (2001). Am. J. Physiol. Lung Cell Mol. Physiol., 280, L823–L838.

  • Cowen T . (2001). Trends Genet., 17, 109–113.

  • Deane NG, Parker MA, Aramandla R, Diehl L, Lee WJ, Washington MK, Nanney LB, Shyr Y and Beauchamp RD . (2001). Cancer Res., 61, 5389–5395.

  • Dragani TA, Manenti G and Delia Porta G . (1986). Cancer Lett., 31, 171–179.

  • Factor VM, Jensen MR and Thorgeirsson SS . (1997). Hepatology, 26, 1434–1443.

  • Fausto N . (1991). Prog. Growth Factor Res., 3, 219–234.

  • Fausto N . (1999). Semin. Liver Dis., 19, 243–252.

  • Fausto N . (2000). J. Hepatol., 32 (Suppl 1), 19–31.

  • Fausto N and Webber EM . (1993). Prog. Liver Dis., 11, 115–137.

  • Frith CH and Ward JM . (1979). J. Environ. Pathol. Toxicol., 3, 329–351.

  • Fry M, Silber J, Loeb LA and Martin GM . (1984). J. Cell Physiol., 118, 225–232.

  • Gavrieli Y, Sherman Y and Ben-Sasson SA . (1992). J. Cell Biol., 119, 493–501.

  • Huang SN and Chisari FV . (1995). Hepatology, 21, 620–626.

  • Isenberg JS, Kolaja KL, Ayoubi SA, Watkins III JB and Klaunig JE . (1997). Carcinogenesis, 18, 1511–1519.

  • Ito T, Mitui H, Udaka NM, Hayyashi HM, Okudela K, Kanisawa M and Kitamura H . (1998). Histochem. Cell Biol., 110, 589–593.

  • Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH and Merlino GT . (1990). Cell, 61, 1137–1146.

  • Kaestner KH, Knochel W and Martinez DE . (2000). Genes Dev., 14, 142.

  • Kanzler S, Meyer E, Lohse AW, Schirmacher P, Henninger J, Galle PR and Blessing M . (2001). Oncogene, 20, 5015–5024.

  • Koike K, Moriya K, Ishibashi K, Matsuura Y, Suzuki T, Saito I, Iino S, Kurokawa K and Miyamura T . (1995). J. Gen. Virol., 76 (Part 12), 3031–3038.

  • Korver W, Roose J and Clevers H . (1997a). Nucleic Acids Res., 25, 1715–1719.

  • Korver W, Roose J, Heinen K, Weghuis DO, de Bruijn D, van Kessel AG and Clevers H . (1997b). Genomics, 46, 435–442.

  • Korver W, Roose J, Wilson A and Clevers H . (1997c). Immunobiology, 198, 157–161.

  • Korver W, Schilham MW, Moerer P, van den Hoff MJ, Dam K, Lamers WH, Medema RH and Clevers H . (1998). Curr. Biol., 8, 1327–1330.

  • Lee GH, Merlino G and Fausto N . (1992). Cancer Res., 52, 5162–5170.

  • Leung TW, Lin SS, Tsang AC, Tong CS, Ching JC, Leung WY, Gimlich R, Wong GG and Yao KM . (2001). FEBS Lett., 507, 59–66.

  • Ly DH, Lockhart DJ, Lerner RA and Schultz PG . (2000). Science, 287, 2486–2492.

  • Mills JJ, Jirtle RL and Boyer IJ . (1997). Liver Regeneration and Carcinogenesis Jirtle RL (ed). Academic Press: New York.

    Google Scholar 

  • Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y, Tsunoda T, Furukawa Y and Nakamura Y . (2001). Cancer Res., 61, 2129–2137.

  • Peraino C, Staffeldt EF and Ludeman VA . (1981). Carcinogenesis, 2, 463–465.

  • Pierce RH, Vail ME, Ralph L, Campbell JS and Fausto N . (2002). Am. J. Pathol., 160, 1555–1560.

  • Pitot HC . (2001). Lancet, 358, 859–860.

  • Pitot HC . (1996). J. Cancer Res. Clin. Oncol., 122, 257–265.

  • Pugh TD, King JH, Koen H, Nychka D, Chover J, Wahba G, He YH and Goldfarb S . (1983). Cancer Res., 43, 1261–1268.

  • Robles SJ and Adami GR . (1998). Oncogene, 16, 1113–1123.

  • Sandgren EP . (1997). Liver Regeneration and Carcinogenesis. Jirtle RL (ed). Academic Press: New York, pp. 257–300.

    Google Scholar 

  • Sandgren EP, Quaife CJ, Pinkert CA, Palmiter RD and Brinster RL . (1989). Oncogene, 4, 715–724.

  • Santoni-Rugiu E, Jensen MR and Thorgeirsson SS . (1998). Cancer Res., 58, 123–134.

  • Santoni-Rugiu E and Thorgeirsson SS . (1998). Liver Growth and Repair. Strain, AJ and Diehl AM (eds). Chapman & Hall: New York, pp. 100–142.

    Book  Google Scholar 

  • Scholzen T and Gerdes J . (2000). J. Cell Physiol., 182, 311–322.

  • Sell S, Hunt JM, Dunsford HA and Chisari FV . (1991). Cancer Res., 51, 1278–1285.

  • Tamano S, Merlino GT and Ward JM . (1994). Carcinogenesis, 15, 1791–1798.

  • Taub R . (1997). Liver Regeneration and Carcinogenesis. Jirtle RL (ed). Academic Press: New York.

    Google Scholar 

  • Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP and Quinn AG . (2002). Cancer Res., 62, 4773–4780.

  • Thorgeirrson SS, Factor VM and Snyderwine EG . (2000). Toxicol. Lett., 112–113, 553–555.

  • Wang X, Hung NJ and Costa RH . (2001a). Hepatology, 33, 1404–1414.

  • Wang X, Kiyokawa H, Dennewitz MB and Costa RH . (2002a). Proc. Natl. Acad. Sci. USA, 99, 16881–16886.

  • Wang X, Krupczak-Hollis K, Tan Y, Dennewitz MB, Adami GR and Costa RH . (2002b). J. Biol. Chem., 277, 44310–44316.

  • Wang X, Quail E, Hung NJ, Tan Y, Ye H and Costa RH . (2001b). Proc. Natl. Acad. Sci. USA, 98, 11468–11473.

  • Webber EM, Wu JC, Wang L, Merlino G and Fausto N . (1994). Am. J. Pathol., 145, 398–408.

  • Yao KM, Sha M, Lu Z and Wong GG . (1997). J. Biol. Chem., 272, 19827–19836.

  • Ye H, Holterman AX, Yoo KW, Franks RR and Costa RH . (1999). Mol. Cell. Biol., 19, 8570–8580.

  • Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG, Roebuck KA and Costa RH . (1997). Mol. Cell. Biol., 17, 1626–1641.

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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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Correspondence to Guy R Adami.

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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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