Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells.
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.
Hara
Shingo
S
Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime 791-0295, Japan.
Nakashiro
Koh-Ichi
K
Klosek
Sebastian K
SK
Ishikawa
Tohru
T
Shintani
Satoru
S
Hamakawa
Hiroyuki
H
D015687:Cell Hypoxia; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000378:metabolism* / Q000473:pathology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019859:Proto-Oncogene Proteins c-met