In previous studies we have demonstrated that transforming growth factor (TGF)-α/c-myc double transgenic mice exhibit an enhanced rate of cell proliferation, accumulate extensive DNA damage, and develop multiple liver tumors between 4 and 8 months of age. To clarify the biochemical events that may be responsible for the genotoxic and carcinogenic effects observed in this transgenic model, several parameters of redox homeostasis in the liver were examined prior to development of hepatic tumors. By 2 months of age, production of reactive oxygen species, determined by the peroxidation-sensitive fluorescent dye, 2′,7′-dichlorofluorescin diacetate, was significantly elevated in TGF-α/c-myctransgenic hepatocytes versus either wild type or c-myc single transgenic cells, and occurred in parallel with an increase in lipid peroxidation. Concomitantly with a rise in oxidant levels, antioxidant defenses were decreased, including total glutathione content and the activity of glutathione peroxidase, whereas thioredoxin reductase activity was not changed. However, hepatic tumors which developed in TGF-α/c-myc mice exhibited an increase in thioredoxin reductase activity and a very low activity of glutathione peroxidase. Furthermore, specific deletions were detected in mtDNA as early as 5 weeks of age in the transgenic mice. These data provide experimental evidence that co-expression of TGF-α and c-myc transgenes in mouse liver promotes overproduction of reactive oxygen species and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-α/c-myc mouse model. In previous studies we have demonstrated that transforming growth factor (TGF)-α/c-myc double transgenic mice exhibit an enhanced rate of cell proliferation, accumulate extensive DNA damage, and develop multiple liver tumors between 4 and 8 months of age. To clarify the biochemical events that may be responsible for the genotoxic and carcinogenic effects observed in this transgenic model, several parameters of redox homeostasis in the liver were examined prior to development of hepatic tumors. By 2 months of age, production of reactive oxygen species, determined by the peroxidation-sensitive fluorescent dye, 2′,7′-dichlorofluorescin diacetate, was significantly elevated in TGF-α/c-myctransgenic hepatocytes versus either wild type or c-myc single transgenic cells, and occurred in parallel with an increase in lipid peroxidation. Concomitantly with a rise in oxidant levels, antioxidant defenses were decreased, including total glutathione content and the activity of glutathione peroxidase, whereas thioredoxin reductase activity was not changed. However, hepatic tumors which developed in TGF-α/c-myc mice exhibited an increase in thioredoxin reductase activity and a very low activity of glutathione peroxidase. Furthermore, specific deletions were detected in mtDNA as early as 5 weeks of age in the transgenic mice. These data provide experimental evidence that co-expression of TGF-α and c-myc transgenes in mouse liver promotes overproduction of reactive oxygen species and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-α/c-myc mouse model. Current knowledge suggests that endogenous oxidants generated by multiple intracellular pathways may be considered as an important class of naturally occurring carcinogens (1Cerutti P.A. Trump B.F. Cancer Cells. 1991; 3: 1-7PubMed Google Scholar, 2Dreher D. Junod A.F. Eur. J. Cancer. 1996; 32A: 30-38Abstract Full Text PDF PubMed Scopus (758) Google Scholar). Reactive oxygen species (ROS) 1The abbreviations used are: ROS, reactive oxygen species; DCFH-DA, 2,7′-dichlorofluorescin diacetate; EGF, epidermal growth factor; Gpx, glutathione peroxidase; 4-HNE, hydroxylalkenals; TGF, transforming growth factor; WT, wild type; bp, base pair(s); PCR, polymerase chain reaction; DCF, 2′,7′-dichlorofluorescein. 1The abbreviations used are: ROS, reactive oxygen species; DCFH-DA, 2,7′-dichlorofluorescin diacetate; EGF, epidermal growth factor; Gpx, glutathione peroxidase; 4-HNE, hydroxylalkenals; TGF, transforming growth factor; WT, wild type; bp, base pair(s); PCR, polymerase chain reaction; DCF, 2′,7′-dichlorofluorescein. are endogenous oxygen-containing molecules formed as normal products during aerobic metabolism (3Chance B. Sies H. Boveris A. Physiol. Rev. 1979; 59: 527-605Crossref PubMed Scopus (4764) Google Scholar). The term encompasses many species including superoxide (O·̄2), hydroxyl (HO⋅), peroxyl (RO2·), and alkoxyl (RO⋅) radicals, and certain nonradicals such as singlet oxygen (1O2) and hydrogen peroxide (H2O2) that can be easily converted into radicals. ROS can produce genetic mutations as well as gross chromosomal alterations and thus contribute to cancer development at initiation, promotion and progression stages (4Cerutti P.A. Lancet. 1994; 344: 862-863Abstract PubMed Scopus (519) Google Scholar, 5Wiseman H. Halliwell B. Biochem. J. 1996; 313: 17-29Crossref PubMed Scopus (1935) Google Scholar). There is also accumulating evidence that oxidative damage to DNA may play a critical role in aging (6Ames B.N. Shigenaga M.K. Ann. N. Y. Acad. Sci. 1992; 663: 85-96Crossref PubMed Scopus (257) Google Scholar, 7Martin G.M. Austad S.N. Johnson T.E. Nat. Genet. 1996; 13: 25-34Crossref PubMed Scopus (536) Google Scholar). In addition, a number of recent studies have demonstrated that ROS at submicromolar levels act as novel intra- and intercellular second messengers and thus modulate various aspects of cellular functions including proliferation, apoptosis and gene expression (8Suzuki Y.J. Forman H.J. Sevanian A. Free Radic. Biol. Med. 1997; 22: 269-285Crossref PubMed Scopus (1250) Google Scholar, 9Nakamura H. Nakamura K. Yodoi J. Annu. Rev. Immunol. 1997; 15: 351-369Crossref PubMed Scopus (987) Google Scholar). New evidence indicates that ligand binding to cell surface receptors linked to tyrosine kinase activity can trigger signal transduction pathways leading to intracellular ROS generation (10Burdon R.H. Free Radic Biol. Med. 1995; 18: 775-794Crossref PubMed Scopus (1049) Google Scholar). An expanding list of extracellular stimuli shown to induce ROS generation in a variety of nonphagocytic cell types includes a number of peptide growth factors such as platelet-derived growth factor (11Krieger-Brauer H.I. Kather H. Biochem. J. 1995; 307: 543-548Crossref PubMed Scopus (67) Google Scholar, 12Sundaresan M. Yu Z.X. Ferrans V.J. Irani K. Finkel T. Science. 1995; 270: 296-299Crossref PubMed Scopus (2285) Google Scholar), basic fibroblast growth factor (11Krieger-Brauer H.I. Kather H. Biochem. J. 1995; 307: 543-548Crossref PubMed Scopus (67) Google Scholar, 12Sundaresan M. Yu Z.X. Ferrans V.J. Irani K. Finkel T. Science. 1995; 270: 296-299Crossref PubMed Scopus (2285) Google Scholar, 13Lo Y.Y. Cruz T.F. J. Biol. Chem. 1995; 270: 11727-11730Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar), and epidermal growth factor (EGF) (14Sundaresan M. Yu Z.X. Ferrans V.J. Sulciner D.J. Gutkind J.S. Irani K. Goldschmidt-Clermont P.J. Finkel T. Biochem. J. 1996; 318: 379-382Crossref PubMed Scopus (437) Google Scholar, 15Bae Y.S. Kang S.W. Seo M.S. Baines I.C. Tekle E. Chock P.B. Rhee S.G. J. Biol. Chem. 1997; 272: 217-221Abstract Full Text Full Text PDF PubMed Scopus (1085) Google Scholar), as well as certain cytokines including tumor necrosis factor-α (13Lo Y.Y. Cruz T.F. J. Biol. Chem. 1995; 270: 11727-11730Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar, 16Meier B. Radeke H.H. Selle S. Younes M. Sies H. Resch K. Habermehl G.G. Biochem. J. 1989; 263: 539-545Crossref PubMed Scopus (567) Google Scholar,17Goossens V. Grooten J. De Vos K. Fiers W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8115-8119Crossref PubMed Scopus (549) Google Scholar), interleukin-1 (16Meier B. Radeke H.H. Selle S. Younes M. Sies H. Resch K. Habermehl G.G. Biochem. J. 1989; 263: 539-545Crossref PubMed Scopus (567) Google Scholar), and transforming growth factor (TGF)-β1 (18Das S.K. Fanburg B.L. Am. J. Physiol. 1991; 261: L249-L254PubMed Google Scholar, 19Shibanuma M. Kuroki T. Nose K. Cell Growth Differ. 1991; 2: 583-591PubMed Google Scholar, 20Ohba M. Shibanuma M. Kuroki T. Nose K. J. Cell Biol. 1994; 126: 1079-1088Crossref PubMed Scopus (429) Google Scholar, 21Thannickal V.J. Hassoun P.M. White A.C. Fanburg B.L. Am. J. Physiol. 1993; 265: L622-L626PubMed Google Scholar, 22Thannickal V.J. Fanburg B.L. J. Biol. Chem. 1995; 270: 30334-30338Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 23Sanchez A. Alvarez A.M. Benito M. Fabregat I. J. Cell. Physiol. 1995; 165: 398-405Crossref PubMed Scopus (55) Google Scholar, 24Sanchez A. Alvarez A.M. Benito M. Fabregat I. J. Biol. Chem. 1996; 271: 7416-7422Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). Although the chemical nature of the ROS generated in response to the activation of various receptors has not been well characterized, H2O2 has been shown to be a major component of ROS in cells treated with EGF, platelet-derived growth factor, or TGF-β1 (12Sundaresan M. Yu Z.X. Ferrans V.J. Irani K. Finkel T. Science. 1995; 270: 296-299Crossref PubMed Scopus (2285) Google Scholar, 14Sundaresan M. Yu Z.X. Ferrans V.J. Sulciner D.J. Gutkind J.S. Irani K. Goldschmidt-Clermont P.J. Finkel T. Biochem. J. 1996; 318: 379-382Crossref PubMed Scopus (437) Google Scholar, 15Bae Y.S. Kang S.W. Seo M.S. Baines I.C. Tekle E. Chock P.B. Rhee S.G. J. Biol. Chem. 1997; 272: 217-221Abstract Full Text Full Text PDF PubMed Scopus (1085) Google Scholar,20Ohba M. Shibanuma M. Kuroki T. Nose K. J. Cell Biol. 1994; 126: 1079-1088Crossref PubMed Scopus (429) Google Scholar, 22Thannickal V.J. Fanburg B.L. J. Biol. Chem. 1995; 270: 30334-30338Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar). 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Cancer Google and exhibited a variety of and biochemical of oxidative enhanced ROS production in contribute to as well as development of the an important of cancer in this model. The of ROS generation in c-myc and TGF-α/c-myc to be determined and to be evidence suggests that in nonphagocytic cells a that is linked to the of and can as a for growth and cytokines (14Sundaresan M. Yu Z.X. Ferrans V.J. Sulciner D.J. Gutkind J.S. Irani K. Goldschmidt-Clermont P.J. Finkel T. Biochem. J. 1996; 318: 379-382Crossref PubMed Scopus (437) Google Scholar, 16Meier B. Radeke H.H. Selle S. Younes M. Sies H. Resch K. Habermehl G.G. Biochem. J. 1989; 263: 539-545Crossref PubMed Scopus (567) Google Scholar, B. A. J. Biochem. J. 1993; PubMed Scopus Google Scholar, 1994; PubMed Scopus Google Scholar, H.I. Kather H. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). 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To knowledge studies provide the biochemical evidence that co-expression of TGF-α and c-myc transgenes in mouse in overproduction of These data the that stimulation of cell in liver the of an of oxidative stress leading to massive DNA damage and acceleration of hepatocarcinogenesis in this model. studies are to the pathways that ROS generation and the nature of the specific ROS responsible for genetic of for and E. for of for with and of of for with
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Factor et al. (1998) studied this question.