RESUMO
BACKGROUND: Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)-extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised. METHODS: Modulation of ERK5 expression or function in human PCa PC3 and PC3-ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT-PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry. RESULTS: Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively). CONCLUSION: Our in vitro, in vivo and clinical data support an important role for the MEK5-ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa.
Assuntos
Proteína Quinase 7 Ativada por Mitógeno/fisiologia , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Animais , Benzamidas/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MAP Quinase Quinase 5/genética , MAP Quinase Quinase 5/metabolismo , MAP Quinase Quinase 5/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Nus , Proteína Quinase 7 Ativada por Mitógeno/genética , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Invasividade Neoplásica , Fenótipo , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/farmacologia , Transfecção , Transplante HeterólogoRESUMO
INTRODUCTION: The magnitude and underlying determinants of socioeconomic inequality in dental flossing are poorly understood in Iran. This study aimed to measure and decompose socioeconomic inequalities in dental flossing in Ravansar, Iran. METHODS: Data of 10,002 individuals aged 35-65 years who participated in the Ravansar Non- communicable Diseases (RaNCD) cohort study in Kermanshah province, western Iran, were analyzed. Based on an asset-based method, socioeconomic status (SES) was measured using principal component analysis (PCA). The concentration index and curve were employed to measure socioeconomic inequality in dental flossing. Decomposition analysis was used to estimate the contribution of each determinant to the overall inequality. RESULTS: Of 10,002 participants, 11.74% were found to practice dental floss. The normalized CI for dental flossing was 0.327 in the entire population, 0.323 in females and 0.329 in males, indicating that the use of dental floss is more concentrated among high-SES individuals. The decomposition analysis indicated that SES (50.58%) and level of education (44.90%) respectively contributed the most to this inequality. Place of residence (10.55%) and age group (2.7%) were the next main contributors, respectively. CONCLUSIONS: We found a low prevalence of dental flossing among participants in RaNCD study. We also observed a relatively high degree of pro-rich inequality in dental flossing. The observed inequality was mainly explained by socioeconomic status, level of education and place of residence. Policy interventions should consider these factors to reduce inequalities in dental flossing.