Induction of hepatocyte growth factor activator gene expression under hypoxia activates the hepatocyte growth factor/c-Met system via hypoxia inducible factor-1 in pancreatic cancer

Yoshihiko Kitajima, Takao Ide, Ohtsuka Takao, Kohji Miyazaki

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76 Citations (Scopus)

Abstract

Hepatocyte growth facor activator (HGFA) is a serine protease that converts hepatocyte growth factor (HGF) into its active form. Our previous study demonstrated that tumor-stromal interaction under hypoxia augments the aggressive invasive features of pancreatic cancer line PK8 through activated HGF/c-Met signaling. The present study investigated whether or not hypoxia increases HGFA expression in PK8 cells and promotes the processing of HGF, and leads to c-Met activation. Moreover, HGFA promoter assays were performed to define whether hypoxia inducible factor-1 alpha (HIF-1α) directly activates the HGFA promoter in a hypoxia-dependent fashion. As a result, hypoxia induced the HGFA mRNA and protein expression in PK8 and the elevation under hypoxia was inhibited by the transfection of HIF-1α siRNA, thus indicating HIF-1α-dependent induction of HGFA. The transfection of siRNA against HGFA to PK8 cells suppressed the conversion to the active HGF, which is secreted from fibroblast MRC5. Furthermore, the phosphorylation of c-Met and cancer invasion of PK8 cells were decreased by the transfection of HGFA siRNA under hypoxia. Using the luciferase reporter system, HIF-1α was shown to transactivate the HGFA promoter under hypoxia. These experiments demonstrated for the first time that HGFA is a novel HIF-1 target gene. Under hypoxia, HGFA might be overexpressed and secreted from pancreatic cancer cells, which contributes to accelerate processing of HGF from fibroblast, resulting in the activation of the c-Met pathway. HGF/HGFA/c-Met recruited between cancer-stromal fibroblasts is activated under hypoxic conditions and therefore might play a central role in the aggressive invasion of pancreatic cancer.

Original languageEnglish
Pages (from-to)1341-1347
Number of pages7
JournalCancer Science
Volume99
Issue number7
DOIs
Publication statusPublished - Jul 1 2008
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

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