title: Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFα.
abstract: Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (Trsp(tG37) ) and/or a cancer driver TGFα transgene. The use of Trsp(tG37) altered selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium levels, separate the effect of diet and selenoprotein status. Mice were maintained on diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. Trsp(tG37) transgenic and TGFα/Trsp(tG37) bi-transgenic mice subjected to selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver tumors was significantly increased in mice carrying the TGFα transgene, while dietary selenium and selenoprotein status did not affect tumor number and multiplicity. However, adenoma and carcinoma size and area were smaller in TGFα transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of selenium. Thus, selenium and selenoprotein deficiencies led to widespread pyogranuloma formation, while high selenium levels inhibited the size of TGFα-induced liver tumors.
authors: Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Mohamed E
authors: ME
authors: Moustafa
authors: Bradley A
authors: BA
authors: Carlson
authors: Miriam R
authors: MR
authors: Anver
authors: Gerd
authors: G
authors: Bobe
authors: Nianxin
authors: N
authors: Zhong
authors: Jerrold M
authors: JM
authors: Ward
authors: Christine M
authors: CM
authors: Perella
authors: Victoria J
authors: VJ
authors: Hoffmann
authors: Keith
authors: K
authors: Rogers
authors: Gerald F
authors: GF
authors: Combs
authors: Ulrich
authors: U
authors: Schweizer
authors: Glenn
authors: G
authors: Merlino
authors: Vadim N
authors: VN
authors: Gladyshev
authors: Dolph L
authors: DL
authors: Hatfield
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D019587:Dietary Supplements; D006099:Granuloma / Q000097:blood / Q000473:pathology*; D007554:Isotopes; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D012345:RNA, Transfer, Amino Acid-Specific / Q000378:metabolism; D012643:Selenium / Q000097:blood / Q000172:deficiency* / Q000627:therapeutic use*; D051140:Selenoproteins / Q000172:deficiency* / Q000378:metabolism; D016211:Transforming Growth Factor alpha
chemical_list: D007554:Isotopes; D020033:Protein Isoforms; D012345:RNA, Transfer, Amino Acid-Specific; D051140:Selenoproteins; D016211:Transforming Growth Factor alpha; C036928:tRNA, selenocysteine-; D012643:Selenium