RESUMO
Fibroblast growth factor receptor-1 (FGFR1) over-expression was broadly found in squamous cancer, where it induced cellular proliferation, differentiation, and metastasis by activating various signaling pathway. However, the role of FGFR1 gene expression in predicting prognosis of Esophageal Squamous Cell Carcinoma (ESCC) and its regulatory function in the progression of ESCC are not well understood. Therefore, we performed an analysis of FGFR1 mRNA expression by quantitative RT-PCR in tumor tissue of 145 patients with ESCC. The relationships between FGFR1 gene expression and clinicopathological parameters, also the prognosis were further examined. Results suggested that higher FGFR1 gene expression predicted worse overall survival (HR = 1.502, 95%[CI] = 1.005-2.246, P = 0.045). Disease-free survival tends to be shorter in patients with higher FGFR1 expression but without statistical significance (HR = 1.398, 95%[CI] = 0.942-2.074, P = 0.096). FGFR1 was up regulated in multiple ESCC cell lines. Subsequent in vitro experiments demonstrated that anti-FGFR1 treatment by PD173074 inhibited TE-1 and EC9706 cell viability along with the attenuation of MEK-ERK signaling pathway. In vivo, PD173074 administration also had shown potent ESCC growth arresting effect. Overall, our study suggested that FGFR1 gene expression could be an independent prognosis predictive factor in patients with ESCC. Anti-FGFR1 inhibited ESCC growth and could be a potential strategy in ESCC targeted therapy.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Idoso , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Nus , Prognóstico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hypoxia-driven changes in the tumor microenvironment facilitate cancer metastasis. In the present study, we investigated the regulatory cross talk between endocytic pathway, hypoxia, and tumor metastasis. Dynamin 2 (DNM2), a GTPase, is a critical mediator of endocytosis. Hypoxia decreased the levels of DNM2. DNM2 promoter has multiple hypoxia-inducible factor (HIF)-binding sites and genetic deletion of them relieved hypoxia-induced transcriptional suppression. Interestingly, DNM2 reciprocally regulated HIF. Inhibition of DNM2 GTPase activity and dominant-negative mutant of DNM2 showed a functional role for DNM2 in regulating HIF. Furthermore, the opposite strand of DNM2 gene encodes miR-199a, which is similarly reduced in cancer cells under hypoxia. miR-199a targets the 3'-UTR of HIF-1α and HIF-2α. Decreased miR-199a expression in hypoxia increased HIF levels. Exogenous expression of miR-199a decreased HIF, cell migration, and metastasis of ovarian cancer cells. miR-199a-mediated changes in HIF levels affected expression of the matrix-remodeling enzyme, lysyloxidase (LOX). LOX levels negatively correlated with progression-free survival in ovarian cancer patients. These results demonstrate a regulatory relationship between DNM2, miR-199a, and HIF, with implications in cancer metastasis.
