Gene interactions and pathways from curated databases and text-mining
Clin Cancer Res 2006, PMID: 17085645

Activation of hypoxia-inducible factor-1alpha is necessary for lysophosphatidic acid-induced vascular endothelial growth factor expression.

Lee, Jangsoon; Park, Soon Young; Lee, Eun Kyung; Park, Chang Gyo; Chung, Hyun Cheol; Rha, Sun Young; Kim, Yong Kee; Bae, Gyu-Un; Kim, Bum Kyeong; Han, Jeung-Whan; Lee, Hoi Young

OBJECTIVE

Lysophosphatidic acid (LPA) plays an important role in mediating cell proliferation, survival, and tumor invasion and angiogenesis. This bioactive phospholipid at the concentration in ascitic fluid stimulates the growth of malignant ovarian tumors by increasing the expression of vascular endothelial growth factor (VEGF). In the present study, we investigated whether LPA activates hypoxia inducible factor-1 (HIF-1), a key transcriptional complex in tumor progression and metastasis, thereby increasing the expression of VEGF.

METHODS

Immunoblotting, reverse transcription-PCR, ELISA, immunofluorescence, and chromatin immunoprecipitation assay were used to examine the expression of VEGF and HIF-1alpha in various cancer cells. Specific HIF-1alpha small interfering RNA was transfected to various cancer cells to determine the role of HIF-1alpha in LPA-induced VEGF expression.

RESULTS

LPA induced expressions of VEGF and HIF-1alpha in OVCAR-3, CAOV-3, PC-3, and SK-Hep1 cells but not in SKOV-3 and Hep-3B cells. In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen-activated protein kinase pathways were required for LPA-induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells. Immunofluorescence microscopy assay showed translocation of HIF-1alpha to nucleus by LPA, and chromatin immunoprecipitation assay revealed the binding of HIF-1alpha to the promoter of VEGF by LPA. Importantly, we found that small interfering RNA-induced reduction of HIF-1alpha expression significantly attenuated VEGF expression by LPA.

CONCLUSIONS

Our results show for the first time that LPA induces VEGF via HIF-1alpha activation and reveal a critical role of HIF-1alpha in LPA-induced cancer cell proliferation and angiogenesis.

Diseases/Pathways annotated by Medline MESH: Neoplasm Invasiveness, Neoplasms, Neovascularization, Pathologic
Document information provided by NCBI PubMed

Text Mining Data

hypoxia inducible factor-1 (HIF-1) → LPA: " In the present study, we investigated whether LPA activates hypoxia inducible factor-1 (HIF-1) , a key transcriptional complex in tumor progression and metastasis, thereby increasing the expression of VEGF "

VEGF ⊣ HIF-1alpha: " Specific HIF-1alpha small interfering RNA was transfected to various cancer cells to determine the role of HIF-1alpha in LPA induced VEGF expression "

VEGF → LPA: " Specific HIF-1alpha small interfering RNA was transfected to various cancer cells to determine the role of HIF-1alpha in LPA induced VEGF expression "

VEGF → LPA: " LPA induced expressions of VEGF and HIF-1alpha in OVCAR-3, CAOV-3, PC-3, and SK-Hep1 cells but not in SKOV-3 and Hep-3B cells "

HIF-1alpha → LPA: " LPA induced expressions of VEGF and HIF-1alpha in OVCAR-3, CAOV-3, PC-3, and SK-Hep1 cells but not in SKOV-3 and Hep-3B cells "

VEGF → p42/p44: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

VEGF → p42/p44: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

VEGF → 3-kinase/Akt/mammalian: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

VEGF → 3-kinase/Akt/mammalian target of rapamycin/p70S6K: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

VEGF → rapamycin/p70S6K: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

VEGF → LPA: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

HIF-1alpha → p42/p44: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

HIF-1alpha → p42/p44: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

HIF-1alpha → 3-kinase/Akt/mammalian: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

HIF-1alpha → 3-kinase/Akt/mammalian target of rapamycin/p70S6K: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

HIF-1alpha → rapamycin/p70S6K: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

HIF-1alpha → LPA: " In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen activated protein kinase pathways were required for LPA induced HIF-1alpha and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells "

VEGF → HIF-1alpha: " Importantly, we found that small interfering RNA induced reduction of HIF-1alpha expression significantly attenuated VEGF expression by LPA "

VEGF → LPA: " Our results show for the first time that LPA induces VEGF via HIF-1alpha activation and reveal a critical role of HIF-1alpha in LPA induced cancer cell proliferation and angiogenesis "

Manually curated Databases

No curated data.