title: Development of lymphoproliferative diseases by hypoxia inducible factor-1alpha is associated with prolonged lymphocyte survival.
abstract: Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. sueokae@cc.saga-u.ac.jp
authors.forename: Eisaburo
authors.initials: E
authors.lastname: Sueoka
authors.forename: Naoko
authors.initials: N
authors.lastname: Sueoka-Aragane
authors.forename: Akemi
authors.initials: A
authors.lastname: Sato
authors.forename: Masaru
authors.initials: M
authors.lastname: Ide
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sotomaru
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kitagawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kubota
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Kei
authors.initials: K
authors.lastname: Nakachi
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D006413:Hematopoietic System / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D019076:Transgenes / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011948:Receptors, Antigen, T-Cell