RESUMEN
The human bacterial pathogen Helicobacter pylori exhibits genotoxic properties that promote gastric carcinogenesis. H. pylori introduces DNA double strand breaks (DSBs) in epithelial cells that trigger host cell DNA repair efforts. Here, we show that H. pylori-induced DSBs are repaired via error-prone, potentially mutagenic non-homologous end-joining. A genome-wide screen for factors contributing to DSB induction revealed a critical role for the H. pylori type IV secretion system (T4SS). Inhibition of transcription, as well as NF-κB/RelA-specific RNAi, abrogates DSB formation. DSB induction further requires ß1-integrin signaling. DSBs are introduced by the nucleotide excision repair endonucleases XPF and XPG, which, together with RelA, are recruited to chromatin in a highly coordinated, T4SS-dependent manner. Interestingly, XPF/XPG-mediated DNA DSBs promote NF-κB target gene transactivation and host cell survival. In summary, H. pylori induces XPF/XPG-mediated DNA damage through activation of the T4SS/ß1-integrin signaling axis, which promotes NF-κB target gene expression and host cell survival.
Asunto(s)
Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Células Epiteliales/metabolismo , Helicobacter pylori/genética , Proteínas I-kappa B/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Línea Celular Tumoral , Supervivencia Celular , Cromatina/química , Cromatina/metabolismo , Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/patología , Helicobacter pylori/crecimiento & desarrollo , Helicobacter pylori/patogenicidad , Interacciones Huésped-Patógeno , Humanos , Proteínas I-kappa B/metabolismo , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Integrina beta1/genética , Integrina beta1/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Inhibidor NF-kappaB alfa , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Nucleares/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional , Sistemas de Secreción Tipo IV/genética , Sistemas de Secreción Tipo IV/metabolismoRESUMEN
An epithelial-mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. EMT also enriches for cancer stem cells (CSC) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive. We here report that EMT confers efficient tumorigenicity to murine breast cancer cells by the upregulated expression of the proangiogenic factor VEGF-A and by increased tumor angiogenesis. On the basis of these data, we propose a novel interpretation of the features of CSCs with EMT-induced, VEGF-A-mediated angiogenesis as the connecting mechanism between cancer cell stemness and tumor initiation.