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.
Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Cell Biology and Anatomy, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
H Artee
HA
Luchman
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Michelle L
ML
Villemaire
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada; Department of Biochemistry, Molecular Biology, and Oncology, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada.
Tarek A
TA
Bismar
Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Bradley A
BA
Carlson
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada. Electronic address: jirik@ucalgary.ca.
Frank R
FR
Jirik
D000818:Animals; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D011467:Prostate / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012345:RNA, Transfer, Amino Acid-Specific / Q000235:genetics*; D051140:Selenoproteins / Q000235:genetics
D012345:RNA, Transfer, Amino Acid-Specific; D051140:Selenoproteins; C036928:tRNA, selenocysteine-