RESUMEN
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) are the major risk factor for developing colitis associated cancer (CAC). Previously, we have reported that Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was overexpressed in colorectal cancer (CRC), but we don't know the role of PIK3R3 in IBD. METHODS: We investigated the differential expression of PIK3R3 and ZO-1 in IBD patients by using Immunohistochemical (IHC) and Gene Expression Omnibus (GEO) database analysis. Caco-2 cells were exposed to different conditions to assess protein level changes of PIK3R3 and ZO-1. Caco-2 cell monolayers were transfected with PIK3R3/siPIK3R3 to assess transepithelial electrical resistance. Tight junction protein integrity was assessed by immunoblot and immunofluorescence. For further, intestinal permeability and tight junction protein integrity were assessed in animal study to assess the treatment role of PIK3R3 specific inhibitor TAT-N 15 (N15). RESULTS: PIK3R3 was increased in IBD patients, and negatively controlled the expression of ZO-1. In vitro, PIK3R3 regulates ZO-1 by activating NF-kB pathway. Overexpression of PIK3R3 in Caco-2 cells decreased transepithelial electrical resistance (TEER), an opposite result was observed in siPIK3R3 cells. In animal study, inhibition of PIK3R3 by N15 contributed to amelioration of DSS-induced intestinal permeability. Mice treated with N15 exhibited less disruption of TJs in colon tissues. CONCLUSIONS: PIK3R3 was increased in clinical IBD patients with accompanying disruption of ZO-1 expression. Inhibition of PIK3R3 attenuated DSS-induced IBD symptoms in a mouse model. These findings indicated that PIK3R3 could be a therapeutic target for IBD.
Asunto(s)
Enfermedades Inflamatorias del Intestino/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína de la Zonula Occludens-1/metabolismo , Animales , Células CACO-2 , Colitis/sangre , Colitis/inducido químicamente , Colitis/inmunología , Colon/metabolismo , Colon/patología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Permeabilidad/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/genética , Ácidos Sulfónicos/administración & dosificación , Ácidos Sulfónicos/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Phosphoinositide-3-kinase regulatory subunit 3(PIK3R3) is overexpressed in different types of human cancer. We previously reported the important role of PIK3R3 in colorectal cancer (CRC). However, the prognosis effect of PIK3R3 in CRC is still remaining unclear. In this study, we explored online clinical databases to analyze the prognosis differences between higher and lower expression of PIK3R3 in CRC patients. Interestingly, we found that better disease-free survival (DFS) were occurred in patients with higher expression of PIK3R3, but there is no significant difference in overall survival (OS). For further, we showed that PIK3R3 could enhance 5-FU induced apoptosis by regulating the expression of thymmidine phosphorylase (TP). In conclusion, PIK3R3 could be considered as a predictor of 5-FU sensitivity for personalized treatment, and a therapeutic target for colorectal cancer.
