RESUMEN
Pulmonary arterial hypertension (PAH) remains a disease with poor prognosis; thus, a new mechanism for PAH treatment is necessary. Circulating nerve growth factor receptor (Ngfr)-positive cells in peripheral blood mononuclear cells are associated with disease severity and the prognosis of PAH patients; however, the role of Ngfr in PAH is unknown. In this study, we evaluated the function of Ngfr using Ngfr gene-deletion (Ngfr-/-) mice. To elucidate the role of Ngfr in pulmonary hypertension (PH), we used Ngfr-/- mice that were exposed to chronic hypoxic conditions (10% O2) for 3 weeks. The development of hypoxia-induced PH was accelerated in Ngfr-/- mice compared to littermate controls. In contrast, the reconstitution of bone marrow (BM) in Ngfr-/- mice transplanted with wild-type BM cells improved PH. Notably, the exacerbation of PH in Ngfr-/- mice was accompanied by the upregulation of pulmonary vascular remodeling-related genes in lung tissue. In a hypoxia-induced PH model, Ngfr gene deletion resulted in PH exacerbation. This suggests that Ngfr may be a key molecule involved in the pathogenesis of PAH.
Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Animales , Ratones , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/patología , Hipoxia/metabolismo , Leucocitos Mononucleares/metabolismo , Pulmón/patología , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/patología , Receptor de Factor de Crecimiento Nervioso/metabolismo , Remodelación VascularRESUMEN
BACKGROUND: The purpose of this study was to investigate the expression and clinical significance of prolactin (PRL), placenta growth factor (PIGF) and nerve growth factor receptor (NGFR) in esophageal squamous cell carcinoma (ESCC). METHODS: PRL, PIGF and NGFR were selected through being screened normal human and esophageal cancer (EC) plasma by high-throughput protein chips. Subsequently, enzyme linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were used to detect the expression in ESCC and control group. Then, its clinical significance was statistically evaluated. RESULTS: The expression of PRL, PIGF and NGFR in plasma and tissue of patients with EC was higher than healthy controls and adjacent tissue, respectively. Among the clinical parameters, the expression of PRL and NGFR protein was correlated with the tumor classification of ESCC (P<0.05), while PIGF protein was correlated with the clinical stage of ESCC (P<0.05). The area under the ROC (AUC) of PRL, PIGF, and NGFR in plasma was 0.69, 0.72, and 0.66 in separately. Furthermore, the combined detection of three proteins had a better AUC of 0.74 with a sensitivity of 66.7% and a specificity of 72.4%. Kaplan-Meier survival analysis revealed that positive expression of PRL, PIGF and NGFR in histological predicted significantly worse overall survival (OS) than negative expression (P<0.05). CONCLUSIONS: PRL, PIGF and NGFR are promising biomarkers for diagnosis and prognosis prediction of ESCC.
RESUMEN
BACKGROUND: The study was aimed to investigate the mechanisms causing acquired chemoresistance to icotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in non-small cell lung cancer (NSCLC). METHODS: Three wildtype NSCLC cell lines were used to produce icotinib-resistant (IR) cell lines. Real-time PCR and western blot assays were used to detect the mRNA and protein levels of nerve growth factor receptor (NGFR) and forkhead box P3 (FOXP3). MTT assay was used to detect the viability of cells. Luciferase activity and chromatin immunoprecipitation (ChIP) assays were used to detect the transactivation activity of FOXP3. RESULTS: NGFR and FOXP3 were dramatically increased in three IR NSCLC cell lines, and both proteins were required for induction of icotinib resistance. NGFR-induced icotinib resistance was partially related to activation of AKT, a well-known chemoresistance inducer in many tumor types. Activated AKT could induce the expression of FOXP3 which further induce icotinib through transactivating NGFR expression by binding to its promoter. In addition, the inducing of FOXP3 could also induce icotinib resistance solely. CONCLUSIONS: NGFR, AKT and FOXP3 form a positive feedback loop, by which the abilities of NGFR and FOXP3 on inducing icotinib resistance are further enhanced. We believe that NGFR and FOXP3 might be novel therapeutic targets in NSCLC.