RESUMEN
Leukemia inhibitory factor receptor (LIFR) has been documented as a cancer promoter and to be present at high levels in various types of tumor tissues. In our search for molecules prognostic of colorectal cancer (CRC), we found high levels of LIFR in CRC tissue samples. Further analyses revealed that LIFR was indeed prognostic of CRC patient survival, and was associated with tumor size, lymphatic metastasis and stages. LIFR was found to promote tumor growth, metastasis and angiogenesis both in vitro and in vivo. High levels of LIFR in CRC facilitated proliferation and migration of endothelial cells, resulting in an increase in angiogenic activity. Moreover, interleukin 8 (IL-8) was found to play a role in the LIFR induced angiogenesis. IL-8 levels were correlated with LIFR levels in CRC tissues, whereas depletion of IL-8 led to a reduced angiogenic activity of LIFR in CRC cells. In addition, LIFR increased phosphorylation level of Erk, which regulates il-8 transcription. We conclude that LIFR is possibly a valuable prognostic marker for CRC. Our results also implicate a mechanism by which LIFR regulates tumor angiogenesis through Erk/IL-8 pathway, and that LIFR could be a potential therapeutic target for CRC.
Asunto(s)
Neoplasias Colorrectales/irrigación sanguínea , Células Endoteliales/patología , Interleucina-8/metabolismo , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/metabolismo , Neovascularización Patológica/patología , Anciano , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Regulación hacia Abajo , Femenino , Estudios de Seguimiento , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-8/genética , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/genética , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neovascularización Patológica/mortalidad , Pronóstico , ARN Interferente Pequeño/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel process using N-benzylhydroxylamine hydrochloride as a "C1N1 synthon" in [2+2+1] cyclization for the construction of 1,2,5-trisubstituted imidazoles has been described for the first time. The key to realizing this process lies in capturing arylamines by in situ generated novel acyl ketonitrone intermediates. Subsequent tautomerization activates the α-C(sp3)-H of N-benzylhydroxylamines, and thus breaks through its inherent reaction mode and achieves N, α-C site-selective cyclization. Furthermore, this method enables scale-up synthesis and late-stage modification of complex molecules.