Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway.
Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast ... cancer, and found that Mel-18 was a novel regulator of HIF-1α. Mel-18 negatively regulated the HIF-1α expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1α expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1α protein level. Mel-18 modulated the HIF-1α transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1α/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1α expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1α and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.
Mesh Terms:
Animals, Breast Neoplasms, Cell Line, Tumor, Female, Forkhead Transcription Factors, Gene Knockdown Techniques, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Inbred NOD, Neovascularization, Pathologic, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinase, Polycomb Repressive Complex 1, Proto-Oncogene Proteins c-akt, Repressor Proteins, Signal Transduction, Transcription, Genetic, Vascular Endothelial Growth Factor A, Xenograft Model Antitumor Assays
Animals, Breast Neoplasms, Cell Line, Tumor, Female, Forkhead Transcription Factors, Gene Knockdown Techniques, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Inbred NOD, Neovascularization, Pathologic, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinase, Polycomb Repressive Complex 1, Proto-Oncogene Proteins c-akt, Repressor Proteins, Signal Transduction, Transcription, Genetic, Vascular Endothelial Growth Factor A, Xenograft Model Antitumor Assays
Oncogene
Date: Nov. 10, 2011
PubMed ID: 21602890
View in: Pubmed Google Scholar
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