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Hypoxia-Independent Overexpression of Hypoxia-Inducible Factor 1 as an Early Change in Mouse Hepatocarcinogenesis

¹ Department of Pathology, Asahikawa Medical College and ² National Hospital Organization, Dohoku National Hospital, Asahikawa, Japan

Requests for reprints: Katsuhiro Ogawa, Department of Pathology, Asahikawa Medical College, 2-1-1-1 Midorigaoka-East, Asahikawa 078-8510, Japan. Phone: 81-166-68-2372; Fax: 81-166-68-2379; E-mail: ogawak{at}asahikawa-med.ac.jp.

Hypoxia-inducible factor 1 (HIF-1) is involved in tumor progression/metastasis and activated in various cancers. Here we show that HIF-1, 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-1 expression was independent of hypoxia. On the other hand, Akt, the pathway of which can up-regulate HIF-1 expression, was activated in the mouse lesions, whereas HIF-1 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-1 expression is dependent on PI3K/Akt signaling. Conversely, HIF-1 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-1, 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-1. However, Akt was not activated by IGF-II or EGF in the HIF-1 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-1 may be important in the progression of hepatocarcinogenesis. (Cancer Res 2006; 66(23): 11263-70)

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