Prostate Epithelium-Specific Deletion of the Selenocysteine tRNA Gene Trsp Leads to Early Onset Intraepithelial Neoplasia

Although various lines of evidence suggest that oxidative stress plays a role in human prostate cancer initiation and progression, there is a paucity of direct evidence for its role in tumor initiation. To begin to address this issue, we developed a novel tumorigenesis model by reducing the expression of multiple selenoproteins (SPs) in mouse prostatic epithelium. This was accomplished via the prostate-specific deletion of Trsp, a gene that encodes a transfer RNA (Sec tRNA) required for the insertion of selenocysteine residues into SPs during their translation. By 6 weeks of age, Trsp-deficient mice exhibited widespread prostatic intraepithelial neoplasia lesions in all prostatic lobes, which then progressed to high-grade dysplasia and microinvasive carcinoma by 24 weeks. In contrast to other murine prostate cancer models, Trsp-deficient mice required neither the deletion of a tumor suppressor nor the transgenic introduction of an oncogene for prostatic intraepithelial neoplasia lesion development. In keeping with the antioxidant functions of several SPs, we found increases in lipid peroxidation markers in Trsp-deficient epithelial cells. This novel model of prostate neoplasia provides evidence for the existence of a selenoprotein or selenoproteins capable of acting as a tumor suppressor in the murine prostate. Although various lines of evidence suggest that oxidative stress plays a role in human prostate cancer initiation and progression, there is a paucity of direct evidence for its role in tumor initiation. To begin to address this issue, we developed a novel tumorigenesis model by reducing the expression of multiple selenoproteins (SPs) in mouse prostatic epithelium. This was accomplished via the prostate-specific deletion of Trsp, a gene that encodes a transfer RNA (Sec tRNA) required for the insertion of selenocysteine residues into SPs during their translation. By 6 weeks of age, Trsp-deficient mice exhibited widespread prostatic intraepithelial neoplasia lesions in all prostatic lobes, which then progressed to high-grade dysplasia and microinvasive carcinoma by 24 weeks. In contrast to other murine prostate cancer models, Trsp-deficient mice required neither the deletion of a tumor suppressor nor the transgenic introduction of an oncogene for prostatic intraepithelial neoplasia lesion development. In keeping with the antioxidant functions of several SPs, we found increases in lipid peroxidation markers in Trsp-deficient epithelial cells. This novel model of prostate neoplasia provides evidence for the existence of a selenoprotein or selenoproteins capable of acting as a tumor suppressor in the murine prostate. Prostate cancer is the second most common cancer in men after skin cancer in the United States, and it has been estimated that approximately 242,000 men were diagnosed with this disease, and that approximately 28,000 men died of this malignancy in 2012 [Surveillance, Epidemiology, and End Results (SEER) Program; http://seer.cancer.gov/statfacts/html/prost.html]. Adequate selenium (Se) levels have long been proposed as one of the factors preventing the development of various types of malignancy (reviewed in Brigelius-Flohe1Brigelius-Flohe R. Selenium compounds and selenoproteins in cancer.Chem Biodivers. 2008; 5: 389-395Crossref PubMed Scopus (104) Google Scholar and Davis et al2Davis C.D. Tsuji P.A. Milner J.A. Selenoproteins and cancer prevention.Annu Rev Nutr. 2012; 32: 73-95Crossref PubMed Scopus (136) Google Scholar) including prostate cancer. Se is an essential dietary micronutrient that is found in association with various organic molecules, including the 21st amino acid, selenocysteine (Sec).3Hatfield D.L. Gladyshev V.N. How selenium has altered our understanding of the genetic code.Mol Cell Biol. 2002; 22: 3565-3576Crossref PubMed Scopus (551) Google Scholar The latter molecule is essential for the normal function of the selenoprotein (SP) family of proteins. Indeed, SP synthesis requires that Sec residues be inserted into the growing polypeptide chains opposite specific UGA codons that are present within the coding regions of SP mRNAs.4Hatfield D.L. Carlson B.A. Xu X.M. Mix H. Gladyshev V.N. Selenocysteine incorporation machinery and the role of selenoproteins in development and health.Prog Nucleic Acid Res Mol Biol. 2006; 81: 97-142Crossref PubMed Scopus (154) Google Scholar Although in the eukaryotic nucleus, UGA ordinarily specifies a translational stop, in the case of the selenoprotein gene coding regions, the UGA codon is recognized by a specific transfer RNA, Sec tRNA (designated Sec tRNA[Ser]Sec), that is encoded by the Trsp gene. Recognition of the appropriate UGA codon(s) in SPs is enabled by a group of proteins that recognize a Sec insertion sequence that is located within the 3′ untranslated regions of SP mRNAs.5Small-Howard A. Morozova N. Stoytcheva Z. Forry E.P. Mansell J.B. Harney J.W. Carlson B.A. Xu X.M. Hatfield D.L. Berry M.J. Supramolecular complexes mediate selenocysteine incorporation in vivo.Mol Cell Biol. 2006; 26: 2337-2346Crossref PubMed Scopus (124) Google Scholar There are 25 human and 24 murine SP genes,6Kryukov G.V. Castellano S. Novoselov S.V. Lobanov A.V. Zehtab O. Guigo R. Gladyshev V.N. Characterization of mammalian selenoproteomes.Science. 2003; 300: 1439-1443Crossref PubMed Scopus (1901) Google Scholar approximately one-third of which function as antioxidants. This family includes the important glutathione peroxidases (GPx) 1 through 47Papp L.V. Lu J. Holmgren A. Khanna K.K. From selenium to selenoproteins: synthesis, identity, and their role in human health.Antioxid Redox Signal. 2007; 9: 775-806Crossref PubMed Scopus (1042) Google Scholar that are responsible for protecting cells against reactive oxygen species (ROS)-mediated and reactive nitrogen species–mediated damage to cellular macromolecules.6Kryukov G.V. Castellano S. Novoselov S.V. Lobanov A.V. Zehtab O. Guigo R. Gladyshev V.N. Characterization of mammalian selenoproteomes.Science. 2003; 300: 1439-1443Crossref PubMed Scopus (1901) Google Scholar Other members of the SP family, such as the thioredoxin reductases, are critical regulators of intracellular redox potential, and thus regulate the activities of redox-sensitive signal transduction molecules and transcription factors.7Papp L.V. Lu J. Holmgren A. Khanna K.K. From selenium to selenoproteins: synthesis, identity, and their role in human health.Antioxid Redox Signal. 2007; 9: 775-806Crossref PubMed Scopus (1042) Google Scholar, 8Patenaude A. Murthy M.R. Mirault M.E. Emerging roles of thioredoxin cycle enzymes in the central nervous system.Cell Mol Life Sci. 2005; 62: 1063-1080Crossref PubMed Scopus (91) Google Scholar Although the function of many SPs is still unknown, other than that they may participate in antioxidant and anabolic processes, the SPs that are most likely to be relevant to an increased cancer risk are those of the GPx family, the 15-kDa selenoprotein (Sep15), and the thioredoxin reductases, previously implicated in various cancers, including prostate cancer (reviewed in Rayman9Rayman M.P. Selenium in cancer prevention: a review of the evidence and mechanism of action.Proc Nutr Soc. 2005; 64: 527-542Crossref PubMed Scopus (694) Google Scholar and Davis2Davis C.D. Tsuji P.A. Milner J.A. Selenoproteins and cancer prevention.Annu Rev Nutr. 2012; 32: 73-95Crossref PubMed Scopus (136) Google Scholar). It has been proposed that SPs may exert protective effects, not only against tumorigenesis, but also against cancer progression and metastasis.10Jiang C. Kim K.H. Wang Z. Lu J. Methyl selenium-induced vascular endothelial apoptosis is executed by caspases and principally mediated by p38 MAPK pathway.Nutr Cancer. 2004; 49: 174-183Crossref PubMed Scopus (43) Google Scholar, 11Ip C. Dong Y. Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland.Anticancer Res. 2001; 21: 863-867PubMed Google Scholar There is evidence of an association between Se and reductions in DNA damage and oxidative stress, together with data showing an effect of SP genotype on cancer risk, thus suggesting that alterations in SP activity may have a role in tumorigenesis (reviewed in Rayman9Rayman M.P. Selenium in cancer prevention: a review of the evidence and mechanism of action.Proc Nutr Soc. 2005; 64: 527-542Crossref PubMed Scopus (694) Google Scholar). To begin to study this possibility, SP levels were reduced via the transgenic expression of a mutant Sec tRNA (i6A−) to determine what effect this would have on prostate tumorigenesis in transgenic mice expressing the SV40 large-T and small-t oncogenes (C3(1)/Tag) in their prostates.12Diwadkar-Navsariwala V. Prins G.S. Swanson S.M. Birch L.A. Ray V.H. Hedayat S. Lantvit D.L. Diamond A.M. Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model.Proc Natl Acad Sci U S A. 2006; 103: 8179-8184Crossref PubMed Scopus (126) Google Scholar Interestingly, the bigenic mice exhibited accelerated tumor development, suggesting that one or more SPs were involved in suppressing tumor evolution. There has been considerable speculation and circumstantial evidence supporting a role for oxidative stress in human prostate cancer.13Oberley T.D. Zhong W. Szweda L.I. Oberley L.W. Localization of antioxidant enzymes and oxidative damage products in normal and malignant prostate epithelium.Prostate. 2000; 44: 144-155Crossref PubMed Scopus (105) Google Scholar, 14Gupta-Elera G. Garrett A.R. Robison R.A. O'Neill K.L. The role of oxidative stress in prostate cancer.Eur J Cancer Prev. 2012; 21: 155-162Crossref PubMed Scopus (94) Google Scholar Although much work implicating ROS has been performed on human prostate cancer cell lines in vitro, as well as in xenografted and transgenic mice,15Ouyang X. DeWeese T.L. Nelson W.G. Abate-Shen C. Loss-of-function of Nkx3.1 promotes increased oxidative damage in prostate carcinogenesis.Cancer Res. 2005; 65: 6773-6779Crossref PubMed Scopus (132) Google Scholar, 16Kumar B. Koul S. Khandrika L. Meacham R.B. Koul H.K. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype.Cancer Res. 2008; 68: 1777-1785Crossref PubMed Scopus (560) Google Scholar there is a paucity of direct evidence in either humans or mice demonstrating that oxidative stress plays a tumor-initiating role in this disease. The targeted removal of Trsp in all tissues was embryonic lethal, indicating that there are one or more SPs that are essential for normal development.17Kumaraswamy E. Carlson B.A. Morgan F. Miyoshi K. Robinson G.W. Su D. Wang S. Southon E. Tessarollo L. Lee B.J. Gladyshev V.N. Hennighausen L. Hatfield D.L. Selective removal of the selenocysteine tRNA [Ser]Sec gene (Trsp) in mouse mammary epithelium.Mol Cell Biol. 2003; 23: 1477-1488Crossref PubMed Scopus (94) Google Scholar Hence, investigation of SP deficiency in vivo has required a conditional (Cre-LoxP) mutagenesis approach. Studying the consequences of tissue-specific Trsp gene loss allows insight into the role of the SP family in any given organ or cell type. Thus, to determine whether prostate-specific deletion of SP would have any effect on the normal murine prostate, we interbred mice carrying loxP-flanked (floxed) Trsp alleles (Trspfl/fl)17Kumaraswamy E. Carlson B.A. Morgan F. Miyoshi K. Robinson G.W. Su D. Wang S. Southon E. Tessarollo L. Lee B.J. Gladyshev V.N. Hennighausen L. Hatfield D.L. Selective removal of the selenocysteine tRNA [Ser]Sec gene (Trsp) in mouse mammary epithelium.Mol Cell Biol. 2003; 23: 1477-1488Crossref PubMed Scopus (94) Google Scholar with mice expressing a prostate-specific Cre transgene.18Wu X. Wu J. Huang J. Powell W.C. Zhang J. Matusik R.J. Sangiorgi F.O. Maxson R.E. Sucov H.M. Roy-Burman P. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation.Mech Dev. 2001; 101: 61-69Crossref PubMed Scopus (294) Google Scholar Our results demonstrate that Trsp deletion in the prostatic epithelium leads to the rapid development of prostatic intraepithelial neoplasia (PIN) lesions. It should be noted that our findings neither contradict nor are made irrelevant by the negative results of the SELECT trial (Selenium and Vitamin E Cancer Prevention Trial).19Dunn B.K. Richmond E.S. Minasian L.M. Ryan A.M. Ford L.G. A nutrient approach to prostate cancer prevention: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).Nutr Cancer. 2010; 62: 896-918Crossref PubMed Scopus (69) Google Scholar This trial, which enrolled men with normal to high Se blood levels at entry, was intended to evaluate whether dietary Se (with and without vitamin E) supplementation would decrease the risk of prostate cancer development. Its purpose was not to demonstrate whether SP levels were relevant to human prostate tumorigenesis. Although generalized SP deficiency leads to the rapid development of PIN lesions in mice, in humans, isolated SP deficiencies would likely exert more subtle effects. It is conceivable nonetheless, and in view of the evidence that oxidative stress may be important to the pathogenesis of the human disease,13Oberley T.D. Zhong W. Szweda L.I. Oberley L.W. Localization of antioxidant enzymes and oxidative damage products in normal and malignant prostate epithelium.Prostate. 2000; 44: 144-155Crossref PubMed Scopus (105) Google Scholar, 14Gupta-Elera G. Garrett A.R. Robison R.A. O'Neill K.L. The role of oxidative stress in prostate cancer.Eur J Cancer Prev. 2012; 21: 155-162Crossref PubMed Scopus (94) Google Scholar, 20Khandrika L. Kumar B. Koul S. Maroni P. Koul H.K. Oxidative stress in prostate cancer.Cancer Lett. 2009; 282: 125-136Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar that our Trsp model represents an abbreviated scenario of a that ordinarily be many in E. Carlson B.A. Morgan F. Miyoshi K. Robinson G.W. Su D. Wang S. Southon E. Tessarollo L. Lee B.J. Gladyshev V.N. Hennighausen L. Hatfield D.L. Selective removal of the selenocysteine tRNA [Ser]Sec gene (Trsp) in mouse mammary epithelium.Mol Cell Biol. 2003; 23: 1477-1488Crossref PubMed Scopus (94) Google Scholar were interbred with a mouse expressing Cre the of a a of the rat prostate-specific that is to X. Wu J. Huang J. Powell W.C. Zhang J. Matusik R.J. Sangiorgi F.O. Maxson R.E. Sucov H.M. Roy-Burman P. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation.Mech Dev. 2001; 101: 61-69Crossref PubMed Scopus (294) Google Scholar Cre expression in the and allows of in the prostatic epithelium. was for the were in a in with on and with by the of were and for for the and the Cre as previously E. Carlson B.A. Morgan F. Miyoshi K. Robinson G.W. Su D. Wang S. Southon E. Tessarollo L. Lee B.J. Gladyshev V.N. Hennighausen L. Hatfield D.L. Selective removal of the selenocysteine tRNA [Ser]Sec gene (Trsp) in mouse mammary epithelium.Mol Cell Biol. 2003; 23: 1477-1488Crossref PubMed Scopus (94) Google Scholar, X. Wu J. Huang J. Powell W.C. Zhang J. Matusik R.J. Sangiorgi F.O. Maxson R.E. Sucov H.M. Roy-Burman P. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation.Mech Dev. 2001; 101: 61-69Crossref PubMed Scopus (294) Google Scholar The of the mice were in in and at were with and and were with for were as and was performed were with after a of and were in and at were against and and and either the mouse or the were as development was performed with and were with was performed at the to The proliferation was as the of cells cells cells were of and mice were was for The of the mice were in in and at were with and the which was performed with the in to the It has been previously that Trsp mice are embryonic M.R. K. S. embryonic by targeted of the mouse selenocysteine tRNA gene Natl Acad Sci U S A. PubMed Scopus Google to prostate-specific deletion of Trsp, we mice with Trsp alleles to a mouse expressing Cre the of a X. Wu J. Huang J. Powell W.C. Zhang J. Matusik R.J. Sangiorgi F.O. Maxson R.E. Sucov H.M. Roy-Burman P. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation.Mech Dev. 2001; 101: 61-69Crossref PubMed Scopus (294) Google Scholar we that prostate-specific of the Trsp gene to a loss of and and and in the prostatic epithelium are in and The reduced selenoprotein expression was as as 6 weeks of of was than that of to recognized by the the translational that is to in the of Sec or to a present in the prostatic epithelium. of was more than that of the selenoprotein the results thus that Cre of the Trsp gene the expression of various SPs in the prostatic of of of to and were a of but at levels than in the other of in a of to and were a of but at levels than in the other of levels of SPs by the transgenic expression of a mutant Sec tRNA (i6A−) in the prostate were previously to accelerated development of prostate cancer in V. Prins G.S. Swanson S.M. Birch L.A. Ray V.H. Hedayat S. Lantvit D.L. Diamond A.M. Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model.Proc Natl Acad Sci U S A. 2006; 103: 8179-8184Crossref PubMed Scopus (126) Google Scholar we whether Trsp in the prostatic epithelium would to of prostate cancer. Indeed, we found that mice and PIN lesions in all of the prostate as as 6 weeks of was with cellular cellular and and and with cellular into the and and cell were the mice the more such that high-grade PIN lesions and more of the were by 24 weeks of and at this exhibited evidence of any Thus, mice between 6 and weeks all of the of prostate cancer with including high-grade PIN lesions and microinvasive in contrast to which exhibited neither of There was progression high-grade lesions and into were to weeks. In results that Trsp and of SPs in the prostatic was to to high-grade PIN lesions and microinvasive of tumorigenesis were by of which and of the in the prostate and of epithelial cells into the A and The was to proliferation in the prostatic epithelium of epithelial cells were found to be for in the of the This was in of mice at 6 weeks of as well as in the epithelium and PIN lesions of mice, at a the prostate is developed and cell is as in the of mice of the in the of a in the of cells The to the of cells in the prostatic epithelium of mice, increased of epithelial cells to To the through which SP loss in PIN development, we performed on the prostate of mice a of against various of found of MAPK A and and and with of the MAPK and Interestingly, MAPK to be present in cells on the regions of the with PIN lesions levels to be increased in cells within the Se and SP levels have been with increased oxidative J. Zhong R. E. Zhang Zhang W.G. Dong H. between oxidative stress and expression in the of Res. 2012; PubMed Scopus Google Scholar, S. S. K. of selenium and on and oxidative stress in Res. PubMed Scopus Google Scholar we whether Trsp would be by markers of oxidative Indeed, we found that increased p38 MAPK E and Although we were not to in and we increases in the levels of the lipid peroxidation markers and and and The latter results were with Trsp loss by oxidative lipid Our study that and mice, not only reduced prostatic epithelial expression of SPs, but also to development of PIN lesions and carcinoma in mice within the of that increased oxidative stress, for to reduced levels of SPs such as and a role in this via the of Indeed, expression of specific SPs in the of the mice was with of the cell proliferation and markers of including and there was increased apoptosis in the of the with an increased of cell likely by the of cell damage and nutrient cells that were within the Although we found increased in p38 a of oxidative stress in the we were to in the levels or of other with oxidative stress such as and This may be to and and in our In of oxidative stress present in the of Trsp-deficient we found an of the lipid peroxidation and of oxidative stress within the prostatic epithelium. not only on but also on (reviewed in R. Vitamin the to be 2009; PubMed Scopus Google and is the antioxidant capable of reducing lipid within all cellular (reviewed in R. Vitamin the to be 2009; PubMed Scopus Google Scholar). The of to on lipid plays a role in against In keeping with this mice were found to be more to oxidative (reviewed in R. Vitamin the to be 2009; PubMed Scopus Google Scholar and et H. W. B. A. H. mice glutathione are against oxidative 2004; PubMed Scopus Google Scholar). found levels of in the of mice, suggesting that deficiency of this SP for the increased and we in the PIN lesions. The widespread of the lesions the of the prostate and their in all Trsp-deficient mice against a such as be oxidative stress were DNA in the was with a of were to This would be in keeping with the of ROS to various J. oxygen species as of signal transduction in Full Text Full Text PDF PubMed Scopus Google Scholar, C. A. H. in mammalian oxidative stress Redox Signal. PubMed Scopus Google Scholar such as the increased levels of MAPK p38 and that we in the PIN lesions. It is a generalized is that or to the of with increased This have for the increased levels of dysplasia and we in the Trsp-deficient of cellular SP activity is to be protective against C.D. Tsuji P.A. Milner J.A. Selenoproteins and cancer prevention.Annu Rev Nutr. 2012; 32: 73-95Crossref PubMed Scopus (136) Google Scholar Although the function of SPs is still unknown, SPs deficiency may to an increased cancer risk members of the GPx family, and the thioredoxin Selenium in cancer prevention: a review of the evidence and mechanism of action.Proc Nutr Soc. 2005; 64: 527-542Crossref PubMed Scopus Google Scholar The loss of Trsp would to deficiencies in all SPs in mouse prostate. Thus, in to there be other SPs to PIN development, and it is conceivable that PIN lesions a specific of SP in view of the of the that a against lipid peroxidation we that reduced levels of it a for PIN lesions in Trsp-deficient deletion of has been to the of Trsp deletion in other cell types J. C. Carlson B.A. S. D. G.W. V. Tessarollo L. L. J. Hatfield D.L. selenoprotein expression is required for development and and J. 2010; PubMed Scopus Google Scholar It thus be that be one of the SPs deficiency promotes PIN development in Trsp-deficient It is that many lines of evidence have to a role for oxidative stress in the pathogenesis of human prostate T.D. Zhong W. Szweda L.I. Oberley L.W. Localization of antioxidant enzymes and oxidative damage products in normal and malignant prostate epithelium.Prostate. 2000; 44: 144-155Crossref PubMed Scopus (105) Google Scholar, 14Gupta-Elera G. Garrett A.R. Robison R.A. O'Neill K.L. The role of oxidative stress in prostate cancer.Eur J Cancer Prev. 2012; 21: 155-162Crossref PubMed Scopus (94) Google Scholar as well as in the progression to A. A. E. K. K. S. cell and to in 2012; Full Text Full Text PDF PubMed Scopus Google Scholar Our results the that oxidative stress may have a direct role in the pathogenesis of and suggest that Se or gene that decrease the activity of SPs, humans to prostate cancer. Indeed, gene or expression of specific SPs have been implicated as factors in human prostate C. F. G. in the human selenoprotein gene determine the of selenoprotein markers to selenium supplementation in a J. 2007; 21: PubMed Scopus Google Scholar, A. C. J. L. E. B. S. J. of selenium and in selenoprotein on prostate cancer risk in a study of Prev. 2010; PubMed Scopus Google Scholar, O. N. F. J. K. Y. R. L. A. is in prostate which results in of against oxidative PubMed Scopus Google Scholar, K.L. H. P. L.A. M.J. J. A study of genetic with selenium and prostate cancer risk and Res. 2010; PubMed Scopus Google Scholar, H. F. M.P. between in selenoprotein and prostate cancer Res. 2008; 68: PubMed Scopus Google Scholar, G. G. K. Nelson J. R. G. or in prostate prostate cancer and Res. 2007; PubMed Scopus Google Scholar for and with of and PIN lesions in and mice are by a in cellular and and By of were in the of Prostate in at 24 weeks is and and

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