期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：220-225
DOI：10.1073/pnas.1421697112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAngiogenesis, the development of blood vessels within a solid tumor, is not only essential for primary tumor growth but also vital for tumor invasion and metastasis. The TP73 gene, a p53-family gene, encodes for both a tumor suppressor, TAp73, and an oncogene, {Delta}Np73. Here we report that TAp73 and {Delta}Np73 have opposing roles in tumor angiogenesis. Loss of TAp73 or upregulation of {Delta}Np73 leads to highly vascularized tumors and is found to correlate with increased angiogenesis in patients with breast cancer. Furthermore, we show that TAp73 suppress proangiogenic cytokines and HIF-1 protein accumulation and that this repression is unleashed on TAp73 loss or {Delta}Np73 up-regulation, thus further fuelling tumor development. The p53-family member TAp73 is known to function as a tumor suppressor and regulates genomic integrity, cellular proliferation, and apoptosis; however, its role in tumor angiogenesis is poorly understood. Here we demonstrate that TAp73 regulates tumor angiogenesis through repression of proangiogenic and proinflammatory cytokines. Importantly, loss of TAp73 results in highly vascularized tumors, as well as an increase in vessel permeability resulting from disruption of vascular endothelial-cadherin junctions between endothelial cells. In contrast, loss of the oncogenic p73 isoform {Delta}Np73 leads to reduced blood vessel formation in tumors. Furthermore, we show that up-regulated {Delta}Np73 levels are associated with increased angiogenesis in human breast cancer and that inhibition of TAp73 results in an accumulation of HIF-1 and up-regulation of HIF-1 target genes. Taken together, our data demonstrate that loss of TAp73 or {Delta}Np73 up-regulation activates the angiogenic switch that stimulates tumor growth and progression.
