RESUMO
Breast cancer is a heterogeneous disease characterized by multiple genetic alterations leading to the activation of growth factor signaling pathways that promote cell proliferation. Platelet-derived growth factor-C (PDGF-C) is overexpressed in various malignancies; however, the involvement of PDGF-C in breast cancers and the mechanisms underlying PDGF-C deregulation remain unclear. Here, we show that PDGF-C is overexpressed in clinical breast cancers and correlates with poor prognosis. PDGF-C up-regulation was mediated by the human embryonic lethal abnormal vision-like protein HuR, which stabilizes the PDGF-C transcript by binding to two predicted AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR). HuR is up-regulated in hydrogen peroxide-treated or ultraviolet-irradiated breast cancer cells. Clinically, HuR levels are correlated with PDGF-C expression and histological grade or pathological tumor-node-metastasis (pTNM) stage. Our findings reveal a novel mechanism underlying HuR-mediated breast cancer progression, and suggest that HuR and PDGF-C are potential molecular candidates for targeted therapy of breast cancers.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas ELAV/genética , Linfocinas/genética , Fator de Crescimento Derivado de Plaquetas/genética , Estresse Fisiológico , Transcrição Gênica , Regulação para Cima/genética , Regiões 3' não Traduzidas/genética , Linhagem Celular Tumoral , Proteínas ELAV/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfocinas/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fator de Crescimento Derivado de Plaquetas/metabolismo , Prognóstico , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Multiple angiogenic factors and inhibitors are becoming potential therapeutic targets for ischemia diseases and cancer. Posttranscriptional regulation through the untranslated region of mRNA is emerging as a critical regulating level in nearly all the biological processes. As a kind of RNA binding proteins, HuR plays important role in augmenting the hypoxic or inflammatory signal, stabilizing the resultant angiogenic factors and promoting the proliferation and migration of endothelial cells. These implicate HuR in the proangiogenic factors mediated angiogenesis in the hypoxia and inflammatory. We consider hypotheses that a more effective angiogenesis can be acquired through strengthened and prolonged effects of angiogenic factors, and that progresses in therapeutic angiogensis might also shed light on the implication of HuR in blocking tumor angiogensis. These considerations may help us to explain HuR as a promising therapeutic target for angiogenesis related disease. It may be a candidate in hypoxia therapy and cancer management.