Hypoxia-Independent Overexpression of Hypoxia-Inducible Factor 1α 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-1A, 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 insulinlike 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-1A expression was independent of hypoxia. On the other hand, Akt, the pathway of which can up-regulate HIF-1A expression, was activated in the mouse lesions, whereas HIF-1A 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-1A expression is dependent on PI3K/Akt signaling. Conversely, HIF-1A 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-1A, 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-1A. However, Akt was not activated by IGF-II or EGF in the HIF-1A 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-1A may be important in the progression of hepatocarcinogenesis.

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

“…Among the 39 upregulated genes in GEO-CR cells, we identified 17 genes involved in the HGF-METdependent pathways (Supplementary Table S1 and Fig. 2A) including MET (31)(32)(33)(34). Moreover, the mRNAs of two EGFR selective ligands were upregulated in GEO-CR cells as compared were GEO cells: TGF-a and heparin-binding EGF-like growth factor (HB-EGF).…”

Angiogenesis in pre-malignant conditions

“…This could have been due to the paucity of experimental cell lines and animal models that are representatives of pre-malignant disease. Appropriate models of pre-malignant lesions are now being developed, which will assist in further understanding of the mechanisms involved (Heppner and Wolman, 1999;Tanaka et al, 2006). A combination of data from human tissue studies and investigations on experimental animal models has increased our understanding of some aspects of angiogenesis initiation in these lesions.…”

“…However, the lesions have no obvious areas of necrosis, suggesting that the upregulation of HIF-1a may be due to non-hypoxic mechanisms. This apparent paradox has been investigated in pre-malignant hepatic lesions (Tanaka et al, 2006). Oxygen tension was measured in vivo within murine pre-neoplastic hepatic lesions, which were shown to overexpress HIF-1a and its transcriptional targets such as VEGF and glut-1.…”

“…Oxygen tension within these lesions was not different from that of normal liver tissue. However, the PI3K/Akt pathway, which can upregulate HIF-1a expression, was activated in these lesions and may be responsible for the non-hypoxic upregulation of HIF-1a expression (Tanaka et al, 2006). The activity of cellular kinases has also been found to be responsible for increased HIF-1a activity in hepatitis C virus (HCV)-infected hepatic cells.…”

Common polymorphisms in the HIF-1αgene confer susceptibility to digestive cancer: a meta-analysis

“…HIF-1α is a transcription factor that enhances many types of gene expression, including the expression of those involved in angiogenesis, cell proliferation, glucose metabolism, erythropoiesis, and cell survival (Tanaka et al, 2006). HIF-1α is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of many factors important for tumor growth (Ryan et al, 2000).…”