RESUMEN
Runt domain transcription factor 3 (RUNX3) is widely regarded as a tumour-suppressor gene inactivated by DNA hypermethylation of its canonical CpG (cytidine-phosphate-guanidine) island (CGI) promoter in gastric cancer (GC). Absence of RUNX3 expression from normal gastric epithelial cells (GECs), the progenitors to GC, coupled with frequent RUNX3 overexpression in GC progression, challenge this longstanding paradigm. However, epigenetic models to better describe RUNX3 deregulation in GC have not emerged. Here, we identify lineage-specific DNA methylation at an alternate, non-CGI promoter (P1) as a new mechanism of RUNX3 epigenetic control. In normal GECs, P1 was hypermethylated and repressed, whereas in immune lineages P1 was hypomethylated and widely expressed. In human GC development, we detected aberrant P1 hypomethylation signatures associated with the early inflammatory, preneoplastic and tumour stages. Aberrant P1 hypomethylation was fully recapitulated in mouse models of gastric inflammation and tumorigenesis. Cell sorting showed that P1 hypomethylation reflects altered cell-type composition of the gastric epithelium/tumour microenvironment caused by immune cell recruitment, not methylation loss. Finally, via long-term culture of gastric tumour epithelium, we revealed that de novo methylation of the RUNX3 canonical CGI promoter is a bystander effect of oncogenic immortalization and not likely causal in GC pathogenesis as previously argued. We propose a new model of RUNX3 epigenetic control in cancer, based on immune-specific, non-CGI promoter hypomethylation. This novel epigenetic signature may have utility in early detection of GC and possibly other epithelial cancers with premalignant immune involvement.
Asunto(s)
Linaje de la Célula/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Metilación de ADN , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Células Cultivadas , Islas de CpG , Mucosa Gástrica/inmunología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Regiones Promotoras Genéticas , Neoplasias Gástricas/patologíaRESUMEN
The lower limbs of 55 paediatric patients, with the diagnosis of hereditary motor sensory neuropathy (HMSN) referred to the Orthotics and Biomechanics Department of Hacettepe University, were assessed for appropriate orthotic intervention. Since in the natural history of HMSN symptoms and complaints are variable there is a wide range of interventions possible. The biomechanics of deforming forces and the consequential incidence of deformities in these 55 children, its orthotic implications and the efficacy of orthotic applications are discussed in detail.