RESUMO
PURPOSE: Epithelial to mesenchymal transition (EMT) plays an important role in acquired resistance to gefitinib in lung cancer. This study aimed to explore the underlying mechanism of gefitinib-induced EMT in lung adenocarcinoma cells harboring EGFR mutation. METHODS: CXC chemokine receptor 4 (CXCR4) expression was determined through qRT-PCR, Western blot and flow cytometry assays in lung cancer cell line (PC9) bearing mutated EGFR. Functional role of CXCR4 was inhibited applying siRNAs as well as the specific antagonist AMD3100. The expression of EMT markers was determined, and the migration of PC9 cells was measured with transwell assay. RESULTS: We found that gefitinib promoted the migratory capacity of PC9 cells in vitro, which correlated with EMT occurrence through upregulation of CXCR4. Blocking CXCR4 significantly suppressed gefitinib-induced enhancement of migration and EMT. Moreover, we determined that the upregulation of CXCR4 by gefitinib was dependent on TGF-ß1/Smad2 signaling activity. CONCLUSIONS: Our study suggested a potential mechanism by which gefitinib induced EMT in cells harboring EGFR mutation through a pathway involving TGF-ß1 and CXCR4. Thus, the combination of CXCR4 antagonist and TGFßR inhibitors might provide an alternative strategy to overcome progression of lung cancer after gefitinib treatment.
Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/genética , Gefitinibe/farmacologia , Neoplasias Pulmonares/patologia , Receptores CXCR4/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adenocarcinoma de Pulmão/genética , Benzilaminas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Ciclamos/farmacologia , Humanos , Neoplasias Pulmonares/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Interferente Pequeno/farmacologia , Receptores CXCR4/antagonistas & inibidores , Proteína Smad2/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: To study the association between metabolic syndrome (MS) and the prognosis of patients with endometrial adenocarcinoma. METHODS: A total of 385 patients with endometrial adenocarcinoma in the Department of Gynecologic Oncology, at the Zhejiang Cancer Hospital in China, between January 2001 and December 2008 were chosen. The deadline for the completion of follow-up was December 2013. The overall survival (OS) of the patients with MS was analyzed by the Kaplan-Meier method. Various clinical characteristics (e.g., clinical and surgical stage, vascular invasion, histological grade, tumor size, age at start of the first treatment, and lymphatic metastasis) related to the prognosis of endometrial adenocarcinoma were also evaluated. RESULTS: A univariate analysis demonstrated that the OS rate of the patients with endometrial adenocarcinoma with MS was significantly worse than that of the patients without MS for all 385 patients (P = 0.001). Multivariate Cox proportional hazards regression analyses showed that stage (P = 0.001), lymphatic metastasis (P = 0.021), and MS (P = 0.049) were independent prognostic factors for endometrial adenocarcinoma. Furthermore, statistical analyses demonstrated that MS was closely related to stage (P = 0.021), grade (P = 0.022), vascular invasion (P = 0.044), tumor size (P = 0.035), and lymphatic metastasis (P = 0.014) but not with age at start of the first treatment (P = 0.188). Finally, according to the univariate analysis of the OS rate of 129 cases of endometrial adenocarcinoma with MS, stage (P = 0.001), vascular invasion (P = 0.049), tumor size >2 cm (P = 0.028), lymphatic metastasis (P = 0.002), and CA19-9 value >37 U/m (P = 0.002) all showed significantly low P values for OS. CONCLUSION: Metabolic syndrome is an independent prognostic factor for endometrial adenocarcinoma.