Regulatory Role of the NF-kB Pathway in Lymphangiogenesis and Breast Cancer Mestatasis
Annual summary rept. 1 Jul -30 Jun 2008
SOUTHERN ILLINOIS UNIV SPRINGFIELD
Pagination or Media Count:
The concept of inflammation-induced lymphangiogenesis i.e., formation of new lymphatic vessels has long been recognized, but the molecular mechanisms remained largely unknown. The two primary mediators of lymphangiogenesis are vascular endothelial growth factor receptor-3 VEGFR-3 and Prox1. The key factors that regulate inflammation-induced transcription are members of the NF-kB family however, the role of NF-kB in regulation of lymphatic-specific genes has not been defined. Here, we identified VEGFR-3 and Prox1 as downstream targets of the NF-kB pathway. In vivo time-course analysis of inflammationinduced lymphangiogenesis showed activation of NF-B followed by sequential upregulation of Prox1 and VEGFR-3 that preceded lymphangiogenesis by 4 and 2 days, respectively. Activation of NF-kB by inflammatory stimuli also elevated Prox1 and VEGFR-3 expression in cultured lymphatic endothelial cells resulting in increased proliferation and migration. We also show that Prox1 synergizes with the p50 of NF-kB to control VEGFR-3 expression. Collectively, our findings suggest that induction of the NF-kB pathway by inflammatory stimuli activates Prox1, and both NF-kB and Prox1 activate the VEGFR-3 promoter leading to increased receptor expression in lymphatic endothelial cells. This, in turn, enhances the responsiveness of pre-existing lymphatic endothelium to VEGFR-3 binding factors, VEGF-C and VEGF-D, ultimately resulting in robust lymphangiogenesis.
- Medicine and Medical Research