RESUMEN
Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-ß (TGFß)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFß through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFß axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.
Asunto(s)
Infecciones por Bacteroidaceae/complicaciones , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Porphyromonas gingivalis/fisiología , Factor de Crecimiento Transformador beta/fisiología , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Animales , Infecciones por Bacteroidaceae/metabolismo , Infecciones por Bacteroidaceae/mortalidad , Infecciones por Bacteroidaceae/patología , Células Cultivadas , Progresión de la Enfermedad , Drosophila , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/microbiología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/microbiología , Carcinoma de Células Escamosas de Esófago/mortalidad , Femenino , Estudios de Seguimiento , Células HCT116 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Transducción de Señal/fisiología , Proteínas Smad/metabolismo , Análisis de Supervivencia , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Adenocarcinoma (ADC) is the most common histological type of lung cancer and its proportion is rising, especially in Asian non-smoking women. Recent studies suggest miR-25 may have diverse effects on the pathogenesis of different types of cancer. However, the role of miR-25 in lung cancer is still unknown. The aim of this study was to investigate the potential clinical value of miR-25 in non-smoking women with lung ADC. PATIENTS AND METHODS: Quantitative RT-PCR was performed to evaluate the expression of miR-25 in 100 lung ADC tumor tissues and matched plasma samples and Pearson correlation tests were used to analyze the relationship between values. Associations of miR-25 expression with clinicopathological features were determined using the Student's t-test. To determine prognostic value, overall survival (OS) was evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazard model. RESULTS: Expression of miR-25 in tissue was found to be associated with lymph node metastasis (P=0.021) and disease stage (P=0.012). Moreover, high miR-25 expression was also associated with poorer overall survival of women with lung ADC (P=0.008). CONCLUSION: Tissue miR-25 expression may be associated with tumor progression and have prognostic implications in female lung ADC patients.