RESUMEN
The human Anterior GRadient 2 (AGR2) protein is an Endoplasmic Reticulum (ER)-resident protein which belongs to the Protein-Disulfide Isomerase (PDI) superfamily and is involved to productive protein folding in the ER. As such AGR2, often found overexpressed in adenocarcinomas, contributes to tumour development by enhancing ER proteostasis. We previously demonstrated that AGR2 is secreted (extracellular AGR2 (eAGR2)) in the tumour microenvironment and plays extracellular roles independent of its ER functions. Herein, we show that eAGR2 triggers cell proliferation and characterize the underlying molecular mechanisms. We demonstrate that eAGR2 enhances tumour cell growth by repressing the tumour suppressor p21CIP1. Our findings shed light on a novel mechanism through which eAGR2 behaves as a growth factor in the tumour microenvironment, independently of its ER function, thus promoting tumour cell growth through repression of p21CIP1. Our results provide a rationale for targeting eAGR2/p21CIP1-based signalling as a potential therapeutic target to impede tumour growth.
Asunto(s)
Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Neoplasias Pulmonares/patología , Mucoproteínas/genética , Mucoproteínas/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Regulación hacia Arriba , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Proliferación Celular , Retículo Endoplásmico/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Transducción de Señal , Microambiente TumoralRESUMEN
Impaired lung development has been demonstrated in neonatal animals exposed to hyperoxia. High lung cys-leukotriene levels may be a contributing factor towards the increase in oxygen toxicity. We investigated the effect of cysteinyl-leukotriene inhibition using the receptor antagonist, montelukast (MK, Singulair), on hyperoxia-induced changes in lung parenchymal structure in neonatal rat pups. Rat pups were exposed to 21% O(2) (air) or 50% O(2) (moderate hyperoxia) from days 1-14 after birth, and were administered the cys-leukotriene receptor antagonist MK (1 mg/kg/day) or normal saline from days 4-14. Somatic growth and morphometric measurements were done on day 15. There was a significant increase in bronchoalveolar lavage fluid cysteinyl-leukotriene levels (+61.9%) when animals were exposed to hyperoxia. O(2) exposure significantly decreased the specific internal surface area by 13%. There was a nonsignificant 5.8% and 19.6% increase in mean chord length and mean alveolar diameter, respectively, as well as an 8.6% decrease in lung volume to body weight ratio. Inhibition of only one arm of the arachidonic-acid cascade by MK was not sufficient to prevent these oxygen-induced changes.