RESUMEN
Among their diverse roles as transcriptional regulators during development and cell fate specification, the RUNX transcription factors are best known for the parts they play in haematopoiesis. RUNX proteins are expressed throughout all haematopoietic lineages, being necessary for the emergence of the first haematopoietic stem cells to their terminal differentiation. Although much progress has been made since their discoveries almost two decades ago, current appreciation of RUNX in haematopoiesis is largely grounded in their lineage-specifying roles. In contrast, the importance of RUNX to immunity has been mostly obscured for historic, technical and conceptual reasons. However, this paradigm is likely to shift over time, as a primary purpose of haematopoiesis is to resource the immune system. Furthermore, recent evidence suggests a role for RUNX in the innate immunity of non-haematopoietic cells. This review takes a haematopoiesis-centric approach to collate what is known of RUNX's contribution to the overall mammalian immune system and discuss their growing prominence in areas such as autoimmunity, inflammatory diseases and mucosal immunity.
Asunto(s)
Subunidades alfa del Factor de Unión al Sitio Principal/metabolismo , Hematopoyesis , Inmunidad , Animales , Autoinmunidad/genética , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Diferenciación Celular , Subunidades alfa del Factor de Unión al Sitio Principal/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunidad Mucosa/genética , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Tejido Linfoide/embriología , Tejido Linfoide/metabolismo , Familia de Multigenes , Células Mieloides/citología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Organogénesis , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timocitos/citología , Timocitos/inmunología , Timocitos/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
RUNX3 functions as a tumor suppressor in the gastric epithelium, where its inactivation is frequently observed during carcinogenesis. We identified IL23A as a RUNX3 target gene in gastric epithelial cells. This was confirmed in a series of in vitro analyses in gastric epithelial cell lines. In elucidating the underlying regulatory network, we uncovered a prominent role for the TNF-α/NF-κB pathway in activating IL23A transcription. Moreover, the activating effect of TNF-α was markedly augmented by the infection of Helicobacter pylori, the primary cause of human gastritis. Of note, H. pylori utilized the CagA/SHP2 pathway to activate IL23A, as well as the induction of the NOD1 pathway by iE-DAP. Importantly, RUNX3 synergized strongly with these physiologically relevant stimuli to induce IL23A. Lastly, we present evidence for the secretion of IL23A by gastric epithelial cells in a form that is distinct from canonical IL-23 (IL23A/IL12B).
Asunto(s)
Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Mucosa Gástrica/metabolismo , Subunidad p19 de la Interleucina-23/metabolismo , Activación Transcripcional , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Línea Celular , Línea Celular Tumoral , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Mucosa Gástrica/microbiología , Helicobacter pylori/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/microbiología , Subunidad p19 de la Interleucina-23/genética , FN-kappa B/metabolismo , Proteína Adaptadora de Señalización NOD1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT). However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3 (-/-) p53 (-/-) murine gastric epithelial (GIF-14) cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-ß1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-ß1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Transición Epitelial-Mesenquimal , Receptores ErbB/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal , Células Madre/metabolismo , Animales , Línea Celular , Transformación Celular Neoplásica/genética , Análisis por Conglomerados , Factor de Crecimiento Epidérmico/farmacología , Transición Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Modelos Biológicos , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal/efectos de los fármacos , Esferoides Celulares , Células Madre/efectos de los fármacos , Transcriptoma , Factor de Crecimiento Transformador beta1/farmacología , Células Tumorales CultivadasRESUMEN
The transcription factor RUNX3 functions as a tumor suppressor in the gastrointestinal epithelium, where its loss is an early event in carcinogenesis. While RUNX3 acts concurrently as a mediator of TGF-ß signaling and an antagonist of Wnt, the cellular changes that follow its loss and their contribution to tumorigenicity are not fully understood. Here, we report that the loss of Runx3 in gastric epithelial cells results in spontaneous epithelial-mesenchymal transition (EMT). This produces a tumorigenic stem cell-like subpopulation, which remarkably expresses the gastric stem cell marker Lgr5. This phenomenon is due to the compounding effects of the dysregulation of the TGF-ß and Wnt pathways. Specifically, Runx3(-/-) p53(-/-) gastric epithelial cells were unexpectedly sensitized for TGF-ß-induced EMT, during which the resultant induction of Lgr5 was enhanced by an aberrantly activated Wnt pathway. These data demonstrate a protective role for RUNX3 in safeguarding gastric epithelial cells against aberrant growth factor signaling and the resultant cellular plasticity and stemness.