title: Low Dose Radiation Causes Skin Cancer in Mice and Has a Differential Effect on Distinct Epidermal Stem Cells.
abstract: The carcinogenic effect of ionizing radiation has been evaluated based on limited populations accidently exposed to high dose radiation. In contrast, insufficient data are available on the effect of low dose radiation (LDR), such as radiation deriving from medical investigations and interventions, as well as occupational exposure that concern a large fraction of western populations. Using mouse skin epidermis as a model, we showed that LDR results in DNA damage in sebaceous gland (SG) and bulge epidermal stem cells (SCs). While the first commit apoptosis upon low dose irradiation, the latter survive. Bulge SC survival coincides with higher HIF-1α expression and a metabolic switch upon LDR. Knocking down HIF-1α sensitizes bulge SCs to LDR-induced apoptosis, while upregulation of HIF-1α in the epidermis, including SG SCs, rescues cell death. Most importantly, we show that LDR results in cancer formation with full penetrance in the radiation-sensitive Patched1 heterozygous mice. Overall, our results demonstrate for the first time that LDR can be a potent carcinogen in individuals predisposed to cancer. Stem Cells 2017;35:1355-1364.
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Revenco
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Lapouge
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Virginie
authors.initials: V
authors.lastname: Moers
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brohée
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Panagiota A
authors.initials: PA
authors.lastname: Sotiropoulou
mesh_terms: D000818:Animals; D002280:Basal Cell Carcinoma / Q000473:pathology; D002470:Cell Survival / Q000528:radiation effects; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D004817:Epidermis / Q000528:radiation effects*; D006579:Heterozygote; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D000072081:Patched-1 Receptor / Q000378:metabolism; D019683:Penetrance; D012627:Sebaceous Glands / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse
keywords: Adult stem cells; Apoptosis; Cancer; Metabolism; Radiation