Summary
The expression of the gene for the iron transport protein transferrin was found to be altered in preneoplastic and neoplastic lesions induced in the rat liver by N-nitrosomorpholine. The total RNA of ten hepatocellular carcinomas (HCC) was investigated by Northern blot analysis using a cDNA-probe comprising 150 bp of the 3′ region and compared with the total hepatic RNA in untreated rats. Seven hepatocellular carcinomas showed slight or pronounced reduction in transferrin expression. In situ hybridization of two additional hepatocellular carcinomas revealed marked reduction in the mRNA level for the transferrin gene compared with the surrounding tissue. In contrast, the majority of early preneoplastic lesions storing excess glycogen and tigroid cell foci expressed increased levels of transferrin mRNA. The loss of glycogen in mixed cell foci, which represent a later stage of hepatocarcinogenesis, was usually accompanied by a decrease in transferrin mRNA suggesting a close relationship between this change in gene expression and cellular dedifferentiation emerging during hepatocarcinogenesis.
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Adrian GS, Korinek BW, Bowman BH, Yang F (1986) The human transferrin gene. 5′ region contains conserved sequences which match the control elements regulated by heavy metals, gluco-corticoids and acute phase reaction. Gene 49:167–175
Aldred AR, Dickson PW, Marley PD, Schreiber G (1987) Distribu-tion of transferrin synthesis in brain and other tissues in the rat. J Biol Chem 262:5293–5297
Angerer L, Angerer RC (1989) In situ hybridization with35S-la-belled RNA probes. DuPont Biotech update 4:1–6
Angerer RC, Cox KH, Angerer LM (1985) In situ hybridization to cellular RNAs. In: Setlow JK, Hollaender A (eds) Genetic engineering vol 7. Plenum Press, New York, pp 43–64
Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (1987) Current protocols in molecular biol-ogy. Greene Publishing Associates and Wiley Interscience, John Wiley & Sons, New York
Bannasch P (1968) The cytoplasm of hepatocytes during carcino-genesis. Recent Results Cancer Research, vol 19. Springer, Hei-delberg, pp 1–100
Bannasch P (1990)a Pathobiology of chemical hepatocarcinogene-sis: Recent progress and perspectives. Part I. Cytomorphologi-cal changes and cell proliferation. J Gastroenterol Hepatol 5:149–159
Bannasch P (1990 b) Pathobiology of chemical hepatocarcinogene-sis: Recent progress and perspectives. Part II. Metabolic and molecular changes. J Gastroenterol Hepatol 5:310–320
Bannasch P, Zerban H (1990) Tumours of the liver. In: Turusov V, Mohr U (eds) Pathology of tumours in laboratory animals, vol 1. Tumours of the Rat, 2nd edition. International Agency for Research on Cancer, Lyon, pp 199–240
Bannasch P, Zerban H (1992) Predictive value of hepatic preneo-plastic lesions as indicators of carcinogenic response. In: Vainio H, Magee P, McGregor D, McMichael AJ (eds) Mechanisms of carcinogenesis in risk identification. IARC Scientific Publica-tions, International Agency for Research on Cancer, Lyon pp 381–419
Bannasch P, Benner U, Enzmann H, Hacker HJ (1985) Tigroid cell foci and neoplastic nodules in the liver of rats treated with a single dose of aflatoxin B1. Carcinogenesis 6:1641–1648
Bannasch P, Hacker HJ, Klimek F, Mayer D, Stumpf H, Zerban H (1991) Cytochemical, microbiochemical and molecular genet-ic analysis of chemical carcinogenesis. Progr Histochem Cyto-chem 23:45–60
Barnes D, Sato G (1980) Serum-free cell culture: a unifying ap-proach. Cell 22:649–655
Bowman BH, Yang F, Adrian GS (1988) Transferrin: evolution and genetic regulation of expression. In: Caspari EW, Scanda-lios JG (eds) Advances in genetics, vol 25. Academic Press, New York, pp 1–38
Brunel F, Ochoa A, Schaeffer E, Boissier F, Guillou Y, Cereghini S, Cohen GN, Zakin MM (1988) Interactions of DN A-binding proteins with the 5′region of the human transferrin gene. J Biol Chem 263:10180–10185
Cereghini S, Blumenfeld M, Yaniv M (1988) A liver-specific factor essential for albumin transcription differs between differentiat-ed and dedifferentiated rat hepatoma cells. Genes Dev 2:957–974
Cereghini S, Yaniv M, Cortese R (1990) Hepatocyte dedifferentia-tion and extinction is accompanied by a block in the synthesis of mRNA coding for the transcription factor HNF1/LFB1. EMBO J 9:2257–2263
Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonucleases. Biochemistry 18:5294–5299
Clayton DF, Darnell JrJE (1983) Changes in liver-specific com-pared to common gene transcription during primary culture of mouse hepatocytes. Mol Cell Biol 3:1552–1561
Cox KH, DeLeon DV, Angerer LM, Angerer RC (1984) Detection of mRNAs in sea urchin embryos by in situ hybridization using asymmetric RNA probes. Dev Biol 101:485–502
Eriksson LC, Torndal U-B, Andersson GN (1989) The regulation of cell-surface receptors in chemical hepatocarcinogenesis. In: Bannasch P, Keppler D, Weber G(eds) Liver cell carcinoma. Kluwer Academic Publishers, Dordrecht Boston London, pp 315–327
Frain M, Swart G, Monaci P, Nicosia A, Stämpfli S, Frank R, Cortese R (1989) The liver-specific transcription factor LF-B1 contains a highly diverged homeobox DNA binding domain. Cell 59:145–157
Isom H, Georgoff I, Salditt-Georgieff M, Darnell Jr JE (1987) Persistence of liver-specific messenger RNA in cultured hepato-cytes: different regulatory events for different genes. J Cell Biol 105:2877–2885
James R, Bradshow RA (1984) Polypeptide growth factors. Annu Rev Biochem 53:259–292
Johnson PF (1990) Transcriptional activators in hepatocytes. Cell Growth Differ 1:47–51
de Jong G, van Dijk JP, Eijk HG (1990) The biology of transferrin. Clin Chim Acta 190:1–46
Kahn A, Levin MJ, Zakin MM, Bloch B (1987) The transferrin gene. In: Guroff G (ed) Oncogenes, genes and growth factors. Wiley, New York, pp 277–309
Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning; a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York
Mayer D, Klimek F, Hacker HJ, Seelmann-Eggebert G, Bannasch P (1989) Carbohydrate metabolism in hepatic preneoplasia. In: Bannasch P, Keppler D, Weber G (eds) Liver Cell Carcinoma. Kluwer Academic Publishers, Dordrecht Boston London, pp 329–347
McKnight KS, Hammer RE, Kuenzel EA, Brister RL (1983) Ex-pression of the chicken transferrin gene in transgenic mice. Cell 34:335–341
Pitot HC (1990) Altered hepatic foci: Their role in murine hepato-carcinogenesis. Annu Rev Pharmacol Toxicol 30:465–500
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: A laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor New York
Sanger F, Nickler S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Stitzel KA, Horn PA, Ezra MF (1990) Spontaneous basophilic foci of hepatocellular alteration in Fischer 344 female rats do not exclude iron. Carcinogenesis 11:2253–2254
Tuil D, Vaulont S, Levin MJ, Munnich A, Monguilewsky M, Bou-ton MM, Brissot P, Dreyfus JC, Kahn A (1985) Transient tran-scriptional inhibition of the transferrin gene by cyclic AMP. FEBS Lett 189:310–314
Williams GM, Klaiber M, Parker SE, Farber E (1976) Nature of early appearing, carcinogen-induced liver lesions resistant to iron accumulation. J Natl Cancer Inst 57:157–165
Yang F, Friedrichs WE, Buchanan JM, Herbert DC, Weaker FJ, Brock JH, Bowman BH (1990) Tissue specific expression of mouse transferrin during development and aging. Mech Age Dev 56:187–197
Yang F, Lum JB, McGill JR, Moore CM, Naylor SL, van Bragt PH, Baldwin WD, Bowman BH (1984) Human transferrin: cDNA characterisation and chromosomal localization. Proc Natl Acad Sci USA 81:2752–2756
Zerban H, Rabes HM, Bannasch P (1989) Sequential changes in growth kinetics and cellular phenotype during hepatocarcino-genesis. J Cancer Res Clin Oncol 115:329–334
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Schiebet, K., Stumpf, H., Zerban, H. et al. Altered transferrin gene expression in preneoplastic and neoplastic liver lesions induced in rats with N-nitrosomorpholine. Virchows Archiv B Cell Pathol 62, 251–257 (1992). https://doi.org/10.1007/BF02899689
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DOI: https://doi.org/10.1007/BF02899689