Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation
| Autor: | Samuel Leibovich, Yanbo Xu, Shanchun Guo, Weiqiang Zhou, Ruben R. Gonzalez-Perez, Amber Watters |
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| Rok vydání: | 2010 |
| Předmět: |
Leptin
Transcriptional Activation Vascular Endothelial Growth Factor A medicine.medical_specialty p38 mitogen-activated protein kinases Biology Article Mice Internal medicine Cell Line Tumor medicine Animals STAT3 Promoter Regions Genetic Regulation of gene expression Gene knockdown Leptin receptor digestive oral and skin physiology NF-kappa B Mammary Neoplasms Experimental Cell Biology NFKB1 Hypoxia-Inducible Factor 1 alpha Subunit Up-Regulation Gene Expression Regulation Neoplastic AP-1 transcription factor Endocrinology Gene Knockdown Techniques Cancer research biology.protein Cytokines Female hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Cellular signalling. 22(9) |
| ISSN: | 1873-3913 |
| Popis: | High levels of VEGF and leptin are strongly linked to worse prognosis of breast cancer. Leptin signalling upregulates VEGF in human and mouse mammary tumor cells (MT), but the specific molecular mechanisms are largely unknown. Pharmacologic and genetic approaches were used to dissect the mechanism of leptin regulation of VEGF protein and mRNA in MT (4T1, EMT6 and MMT). A series of VEGF-promoter Luc-reporters (full-length and transcription factor-binding deletions) were transfected into MT to analyze leptin regulation of VEGF transcription. Deletion analysis of VEGF promoter and RNA knockdown shows that HIF-1alpha and NFkappaB are essentials for leptin regulation of VEGF. Leptin activation of HIF-1alpha was mainly linked to canonic (MAPK, PI-3K) and non-canonic (PKC, JNK and p38 MAP) signalling pathways. Leptin non-canonic signalling pathways (JNK, p38 MAP and to less extent PKC) were linked to NFkappaB activation. SP1 was involved in leptin regulation of VEGF in 4T1 cells. AP1 was not involved and AP2 repressed leptin-induced increase of VEGF. Overall, these data suggest that leptin signalling regulates VEGF mainly through HIF-1alpha and NFkappaB. These results delineate a comprehensive mechanism for leptin regulation of VEGF in MT. Disruption of leptin signalling could be used as a novel way to treat breast cancer. |
| Databáze: | OpenAIRE |
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