Hypoxia-inducible factor-1alpha suppresses squamous carcinogenic progression and epithelial-mesenchymal transition.
Hypoxia-inducible factor-1 (HIF-1) is a known cancer progression factor, promoting growth, spread, and metastasis. However, in selected contexts, HIF-1 is a tumor suppressor coordinating hypoxic cell cycle suppression and apoptosis. Prior studies focused on HIF-1 function in established malignancy; however, little is known about its role during the entire process of carcinogenesis from neoplasia induction to malignancy. Here, we tested HIF-1 gain of function during multistage murine skin chemical carcinogenesis in K14-HIF-1alpha(Pro402A564G) (K14-HIF-1alphaDPM) transgenic mice. Transgenic papillomas appeared earlier and were more numerous (6 +/- 3 transgenic versus 2 +/- 1.5 nontransgenic papillomas per mouse), yet they were more differentiated, their proliferation was lower, and their malignant conversion was profoundly inhibited (7% in transgenic versus 40% in nontransgenic mice). Moreover, transgenic cancers maintained squamous differentiation whereas epithelial-mesenchymal transformation was frequent in nontransgenic malignancies. Transgenic basal keratinocytes up-regulated the HIF-1 target N-myc downstream regulated gene-1, a known tumor suppressor gene in human malignancy, and its expression was maintained in transgenic papillomas and cancer. We also discovered a novel HIF-1 target gene, selenium binding protein-1 (Selenbp1), a gene of unknown function whose expression is lost in human cancer. Thus, HIF-1 can function as a tumor suppressor through transactivation of genes that are themselves targets for negative selection in human cancers.
Scortegagna
Marzia
M
Urology Division, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
Martin
Rebecca J
RJ
Kladney
Raleigh D
RD
Neumann
Robert G
RG
Arbeit
Jeffrey M
JM
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051137:Selenium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D014162:Transfection; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D015127:9,10-Dimethyl-1,2-benzanthracene; D002273:Carcinogens; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D051137:Selenium-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497443:Hif1a protein, mouse; C495176:Selenbp1 protein, mouse