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Oral Oncol. 2006 Jul;42(6):593-8. Epub 2006 Feb 15.

Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells.

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  • 1Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime 791-0295, Japan.


Hypoxia increases the invasive and metastatic potential of tumor cells. Increased expression of c-Met/hepatocyte growth factor (HGF)-receptor protein in response to hypoxia in thyroid papillary carcinomas is hypoxia-inducible factor-1 (HIF-1) dependent. Both HGF and c-Met are expressed in human salivary gland cancers. In the current study, we tested whether c-Met expression was regulated by hypoxia and HIF-1alpha using two human salivary gland cancer cell lines: GFP-ACC2 and GFP-ACCM. Hypoxia enhanced the expression of HIF-1alpha in both cell lines, whereas c-Met was markedly induced only in the GFP-ACCM cells, which have metastatic potential. In the latter, hypoxia also promoted HGF-induced invasiveness. Synthetic small-interfering RNA specific for HIF-1alpha inhibited HIF-1alpha expression in the GFP-ACCM cells, and also suppressed the increase in c-Met expression and HGF-induced invasiveness under hypoxic conditions. These results suggest that hypoxia activates the HGF/c-Met system via HIF-1alpha in human salivary gland cancers and might be involved in their metastasis.

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