| RRC ID |
43333
|
| 著者 |
Kitajima Y, Ide T, Ohtsuka T, Miyazaki K.
|
| タイトル |
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.
|
| ジャーナル |
Cancer Sci
|
| 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-1alpha) 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-1alpha siRNA, thus indicating HIF-1alpha-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-1alpha 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.
|
| 巻・号 |
99(7)
|
| ページ |
1341-7
|
| 公開日 |
2008-7-1
|
| DOI |
10.1111/j.1349-7006.2008.00828.x
|
| PII |
CAS828
|
| PMID |
18422749
|
| MeSH |
Cell Hypoxia
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Hepatocyte Growth Factor / metabolism*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
Neoplasm Invasiveness
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology
Phosphorylation
Promoter Regions, Genetic
RNA, Small Interfering / pharmacology
Serine Endopeptidases / genetics*
|
| IF |
4.966
|
| 引用数 |
73
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
MRC-5 |
