title: Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis.
abstract: Hypoxia-inducible factor 1 (HIF-1) is involved in tumor progression/metastasis and activated in various cancers. Here we show that HIF-1alpha, which plays a major role in HIF-1 activation, is overexpressed in preneoplastic hepatocytic lesions from a very early stage during hepatocarcinogenesis in mice and man. Transcriptional targets of HIF-1, such as vascular endothelial growth factor, glut-1, c-met, and insulin-like growth factor II (IGF-II), were also overexpressed in mouse lesions. Oxygen tension within the lesions was not different from that of the normal hepatic tissues, indicating that HIF-1alpha expression was independent of hypoxia. On the other hand, Akt, the pathway of which can up-regulate HIF-1alpha expression, was activated in the mouse lesions, whereas HIF-1alpha was markedly down-regulated in the mouse hepatocellular carcinoma (HCC) cell lines after treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, indicating that HIF-1alpha expression is dependent on PI3K/Akt signaling. Conversely, HIF-1alpha knockdown by short interfering RNA in the HCC cell line resulted in decreased expression of activated Akt together with the HIF-1 target genes, indicating that Akt activation is reversely dependent on HIF-1 activation. Treating the HCC cells with IGF-II or epidermal growth factor (EGF) up-regulated both phospho-Akt and HIF-1alpha, whereas inhibition of IGF-II or EGF signaling down-regulated them both, suggesting that IGF-II and EGF can, at least in part, mediate the activation of Akt and HIF-1alpha. However, Akt was not activated by IGF-II or EGF in the HIF-1alpha knockdown cells, indicating that expression of the HIF-1 target genes is necessary for the Akt activation. These findings suggest that the reciprocal activation of PI3K/Akt signaling and HIF-1alpha may be important in the progression of hepatocarcinogenesis.
authors.affiliation: Department of Pathology, Asahikawa Medical College, Dohoku National Hospital, Asahikawa, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Norikazu
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyakoshi
authors.forename: Susumu
authors.initials: S
authors.lastname: Tamakawa
authors.forename: Masumi
authors.initials: M
authors.lastname: Yoshie
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tokusashi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yaginuma
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007335:Insulin-Like Growth Factor II; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D042461:Vascular Endothelial Growth Factor A; C495678:Slc2a1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one