title: Intermittent induction of HIF-1α produces lasting effects on malignant progression independent of its continued expression.
abstract: Dysregulation of hypoxia-inducible transcription factors HIF-1α and HIF-2α correlates with poor prognosis in human cancers; yet, divergent and sometimes opposing activities of these factors in cancer biology have been observed. Adding to this complexity is that HIF-1α apparently possesses tumor-suppressing activities, as indicated by the loss-of-function mutations or even homozygous deletion of HIF1A in certain human cancers. As a step towards understanding this complexity, we employed 8-week intermittent induction of a stable HIF-1α variant, HIF1α(PP), in various cancer cell lines and examined the effects on malignant progression in xenografts of immunocompromised mice in comparison to those of HIF2α(PP). Although 8-week treatment led to eventual loss of HIF1α(PP) expression, treated osteosarcoma U-2 OS cells acquired tumorigenicity in the subcutaneous tissue. Furthermore, the prior treatment resulted in widespread invasion of malignant glioma U-87 MG cells in the mouse brain and sustained growth of U-118 MG glioma cells. The lasting effects of HIF-1α on malignant progression are specific because neither HIF2α(PP) nor β-galactosidase yielded similar effects. By contrast, transient expression of HIF1α(PP) in U-87 MG cells or constitutive expression of HIF1α(PP) but not HIF2α(PP) in a patient-derived glioma sphere culture inhibited tumor growth and spread. Our results indicate that intermittent induction of HIF-1α produces lasting effects on malignant progression even at its own expense.
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: David L
authors.initials: DL
authors.lastname: Gillespie
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Shauna
authors.initials: S
authors.lastname: Berg
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rice
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Couldwell
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jensen
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, United States of America; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: L Eric
authors.initials: LE
authors.lastname: Huang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness; D013752:Tetracycline / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013752:Tetracycline; D000099162:Endothelial PAS Domain-Containing Protein 1