論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5 |