RESUMEN
Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.
Asunto(s)
Ciclo Celular/fisiología , Supervivencia Celular/fisiología , Colitis , Receptor gp130 de Citocinas/metabolismo , Enterocitos/fisiología , Neoplasias , Factor de Transcripción STAT3/metabolismo , Animales , Apoptosis/fisiología , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Colitis/complicaciones , Colitis/inmunología , Colitis/patología , Receptor gp130 de Citocinas/genética , Enterocitos/citología , Enterocitos/patología , Humanos , Inflamación/inmunología , Interleucina-11/inmunología , Interleucina-6/inmunología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ratones , Neoplasias/etiología , Neoplasias/inmunología , Neoplasias/patología , Regeneración/fisiología , Factor de Transcripción STAT3/genética , Transducción de Señal/fisiologíaRESUMEN
Orf virus (ORFV) is the type species of the Parapoxvirus genus. Here, we present the genomic sequence of the most well studied ORFV isolate, strain NZ2. The NZ2 genome is 138 kbp and contains 132 putative genes, 88 of which are present in all analyzed chordopoxviruses. Comparison of the NZ2 genome with the genomes of 2 other fully sequenced isolates of ORFV revealed that all 3 genomes carry each of the 132 genes, but there are substantial sequence variations between isolates in a significant number of genes, including 9 with inter-isolate amino acid sequence identity of only 38-79%. Each genome has an average of 64% G+C but each has a distinctive pattern of substantial deviation from the average within particular regions of the genome. The same pattern of variation was also seen in the genome of another parapoxvirus species and was clearly unlike the uniform patterns of G+C content seen in all other genera of chordopoxviruses. The availability of genomic sequences of three orf virus isolates allowed us to more accurately assess likely coding regions and thereby revise published data for 24 genes and to predict two previously unrecognized genes.