Journal Article

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

Kim, H-J, Shin, D-H, Park, J-H, Jang, K-S, Lee, J-Y, Kong, Gu

2011

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 631/208/200 / 631/67/2328 / 631/80/86 / 692/699/67/1347 / AKT protein / Angiogenesis / Animals / Apoptosis / Biological and medical sciences / Breast cancer / Breast Neoplasms - blood supply / Breast Neoplasms - pathology / Cancer / Cell Biology / Cell differentiation, maturation, development, hematopoiesis / Cell Line, Tumor / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Chromosome 10 / Data processing / Development and progression / Endothelial cells / Female / Forkhead Box Protein O3 / Forkhead Transcription Factors - metabolism / FOXO3 protein / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Knockdown Techniques / Genetic aspects / Human Genetics / Humans / Hypoxia-inducible factor 1 alpha / Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-inducible factor 1a / Internal Medicine / MDM2 protein / Medicine / Medicine & Public Health / Mice / Mice, Inbred NOD / Molecular and cellular biology / Neovascularization, Pathologic - genetics / Oncology / original-article / Phosphatidylinositol 3-Kinase - metabolism / Physiological aspects / Polycomb Repressive Complex 1 / Promoters / Proto-Oncogene Proteins c-akt - metabolism / PTEN Phosphohydrolase - metabolism / PTEN protein / Repressor Proteins - genetics / Repressor Proteins - metabolism / Signal Transduction / Tensin / Transcription / Transcription, Genetic / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - biosynthesis / Vascular Endothelial Growth Factor A - genetics / Xenograft Model Antitumor Assays / Xenografts