RESUMEN

Objective: The purpose of the study is to explore the mechanism of NRAGE enhancing radioresistance of esophageal squamous cell carcinoma (ESCC) in 2D and 3D levels. Methods: Stably NRAGE-overexpressed ESCC cells and 3D-printing models for ESCC cells were established. Then, cellular malignancy indexes, such as cell morphology, proliferation, radioresistance, motility, apoptosis, cell cycle, and proteins of the Wnt/ß-catenin pathway, were compared between radioresistant and its parental cells in 2D and 3D levels. Additionally, 44 paraffin ESCC specimens with radical radiotherapy were selected to examine NRAGE and ß-catenin protein expression and analyze the clinical correlation. Results: Experiments in 2D culture showed that morphology of the Eca109/NRAGE cells was more irregular, elongated spindle-shaped and disappeared polarity. It obtained faster growth ability, stronger resistance to irradiation, enhanced motility, reduced apoptosis ratio and cell cycle rearrangement. Moreover, Western blot results showed ß-catenin, p-Gsk-3ß and CyclinD1 expressions were induced, while p-ß-catenin and Gsk-3ß expressions decreased in Eca109/NRAGE cells. Experiments in the 3D-printing model showed Eca109/NRAGE cell-laden 3D scaffolds had the advantage on growth and spheroiding according to the brightfield observation, scanning electron microscopy and Ki-67 IHC staining, and higher expression at the ß-catenin protein. Clinical analysis showed that NRAGE expression was higher in tumor tissues than in control tissues of ESCC patients from the Public DataBase. Compared with radiotherapy effective group, both NRAGE total and nuclear and ß-catenin nuclear expressions were significantly upregulated from ESCC specimens in invalid group. Further analysis showed a positive and linear correlation between NRAGE nuclear and ß-catenin nuclear expressions. Additionally, results from univariate and multivariate analyses revealed NRAGE nuclear expression could serve as a risk factor for ESCC patients receiving radical radiotherapy. Conclusion: ESCC cells with NRAGE nuclear accumulation demonstrated greater radioresistance, which may be related to the activation of the Wnt/ß-catenin signaling pathway. It indicated that NRAGE nuclear expression was a potential biomarker for monitoring radiotherapeutic response.

RESUMEN

Background: NRAGE (neurotrophin receptor-interacting melanoma antigen-encoding gene homolog) has a complex role and regulates cell growth in different tumor cells. Although NRAGE was been discovered for more than 10 years ago, the function of NRAGE in hepatoblastoma (HB) cells is currently unknown. Materials and Methods: The expression of NRAGE was detected by reverse transcription-quantitative polymerase chain reaction assay or western blotting assay. Cellular apoptosis was analyzed to estimate the effect of NRAGE under radiation. The ability of clonogenic capacity was evaluated to confirm the influence of proliferation for NRAGE by radiation. The immunofluorescence assay was used to further study the expression of NRAGE under radiation. A nude mouse tumor xenograft model was constructed to confirm the effect of NRAGE deficiency under radiation conditions in vivo. Results: The authors determined that deletion of NRAGE significantly inhibited HB cell proliferation in vitro and in vivo, and NRAGE knockdown apparently sensitized HB cells to ionizing radiation (IR). Further mechanistic studies revealed that NRAGE plays a critical role in homologous recombination by inhibiting the expression of RNF8 (ring finger protein 8) and BARD1 (BRCA1 associated RING domain 1) and the recruitment of RAD51. Conclusions: The authors demonstrated that downregulation of NRAGE sensitizes HB cell lines to IR in vitro and in vivo. It provides a promising therapeutic strategy for HB patients by specifically targeting NRAGE.

Asunto(s)

Antígenos de Neoplasias/biosíntesis , Hepatoblastoma/genética , Hepatoblastoma/radioterapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/radioterapia , Proteínas de Neoplasias/biosíntesis , Reparación del ADN por Recombinación , Animales , Antígenos de Neoplasias/genética , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Células HEK293 , Células Hep G2 , Hepatoblastoma/metabolismo , Hepatoblastoma/patología , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transfección , Proteínas de Motivos Tripartitos/antagonistas & inhibidores , Proteínas de Motivos Tripartitos/biosíntesis , Proteínas de Motivos Tripartitos/genética , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/biosíntesis , Ubiquitina-Proteína Ligasas/genética

RESUMEN

PURPOSE: Neurotrophin receptor-interacting MAGE homologue (Nrage) plays an important role in bone development and the metabolism of normal skeletal structures. Our previous study showed that Nrage inhibited the odontogenic differentiation of mouse dental pulp cells. However, the potential roles and mechanism of Nrage in regulating odontogenic differentiation are unknown. The aim of this study was to investigate the molecular mechanism of Nrage in odontogenic differentiation of mouse odontoblast-like cells. MATERIALS AND METHODS: Endogenous expression of Nrage was stably downregulated by lentivirus-mediated shRNA. Mineralized nodules formation was detected by alizarin red S staining. Dmp-1, Dspp, and ALP mRNA and protein levels were detected by qRT-PCR and western blotting, respectively. In addition, ALPase activity was detected. Confocal microscopy and co-immunoprecipitation (co-IP) were used to analyze the interactions between NRAGE and NF-κB signaling molecules. An IKK inhibitor was also used in the study. RESULTS: NRAGE expression in odontoblasts was downregulated during mouse first maxillary molar development. Moreover, NRAGE expression was downregulated during odontogenic differentiation of odontoblast-like cells. NRAGE knockdown significantly upregulated DMP1 and DSP expression, increased ALPase activity, and promoted mineralized nodule formation. In addition, NRAGE knockdown increased the translocation of NF-κB1 to the nucleus and phosphorylation levels of p65. Co-IP results showed that NRAGE bound to IKKß. Most importantly, the promoting effect of Nrage knockdown on odontoblastic differentiation was reduced after treatment with an IKK inhibitor. CONCLUSIONS: Our data confirmed that NRAGE is an important regulator of odontogenic differentiation of odontoblasts by inhibiting the NF-κB signaling pathway through binding to IKKß. ABBREVIATIONS: Nrage: neurotrophin receptor-interacting MAGE homologue; DSP: dentin sialophospho protein; DMP-1: dentin matrix protein-1; BMP: bone morphogenetic protein; Wnt: wingless; NF-κB: nuclear factor of activated B cells; DAPI: 4',6-diamidino-2-phenylindole; KO: knockout; DPCs: dental pulp cells; AA: ascorbic acid; ß-Gly: ß-glycerophosphate; Dex: dexamethasone; co-IP: co-immunoprecipitation; IκB: inhibitor of NF-κB; IKK: IκB kinase.

Asunto(s)

Diferenciación Celular , Técnicas de Silenciamiento del Gen , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Odontoblastos/citología , Odontoblastos/metabolismo , Odontogénesis , Transducción de Señal , Fosfatasa Alcalina/metabolismo , Animales , Biomarcadores/metabolismo , Calcificación Fisiológica , Diferenciación Celular/genética , Línea Celular , Regulación hacia Abajo/genética , Proteínas de la Matriz Extracelular/metabolismo , Quinasa I-kappa B/metabolismo , Ratones Endogámicos C57BL , Proteínas de Neoplasias/genética , Odontogénesis/genética , Unión Proteica

RESUMEN

Objective To detect the expression of NRAGE protein in esophageal squamous cell carcinoma and investigate the relationship between NRAGE and therapeutic effect of radiotherapy.Methods The expression level of NRAGE in 44 patients with esophageal squamous cell carcinoma was evaluated by immunohistochemistry and statistically analyzed along with clinical data by using multivariate analysis using Cox regression model.Results The overall expression level of NRAGE protein in esophageal squamous cell carcinoma (P=0.025) and the expression level of NRAGE nuclear protein (P=0.008) were negatively correlated with short-term efficacy.In terms of the overall expression level of NRAGE protein,the 3-year survival rates in the strongly positive group and the positive weakly positive group were 16％ and 36％(P=0.198).As for the expression of NRAGE nuclear protein,the 3-year survival rates in the strongly positive group and the positive+ weakly positive group were 0％ and 41％(P＜0.001).Multivariate analysis using Cox regression model demonstrated that as for the expression of NRAGE nuclear protein,the risk of death in the strongly positive group was significantly higher than those in the positive+ weakly positive group (P=0.002).Conclusion The overall expression level of NRAGE protein in the esophageal cancer is negatively correlated with the short-term efficacy of radiotherapy,whereas it is not correlated with long-term survival rate.The strongly positive expression level of NRAGE nuclear protein is negatively correlated with the shortterm efficacy of radiotherapy and the long-term survival rate,prompting that NRAGE may be a molecular indicator for predicting radiation resistance and even the efficacy of radiotherapy for esophageal squamous cell carcinoma

RESUMEN

Objective@#To detect the expression of NRAGE protein in esophageal squamous cell carcinoma and investigate the relationship between NRAGE and therapeutic effect of radiotherapy.@*Methods@#The expression level of NRAGE in 44 patients with esophageal squamous cell carcinoma was evaluated by immunohistochemistry and statistically analyzed along with clinical data by using multivariate analysis using Cox regression model.@*Results@#The overall expression level of NRAGE protein in esophageal squamous cell carcinoma (P=0.025) and the expression level of NRAGE nuclear protein (P=0.008) were negatively correlated with short-term efficacy. In terms of the overall expression level of NRAGE protein, the 3-year survival rates in the strongly positive group and the positive weakly positive group were 16% and 36%(P=0.198). As for the expression of NRAGE nuclear protein, the 3-year survival rates in the strongly positive group and the positive+ weakly positive group were 0% and 41%(P<0.001). Multivariate analysis using Cox regression model demonstrated that as for the expression of NRAGE nuclear protein, the risk of death in the strongly positive group was significantly higher than those in the positive+ weakly positive group (P=0.002).@*Conclusion@#The overall expression level of NRAGE protein in the esophageal cancer is negatively correlated with the short-term efficacy of radiotherapy, whereas it is not correlated with long-term survival rate. The strongly positive expression level of NRAGE nuclear protein is negatively correlated with the short-term efficacy of radiotherapy and the long-term survival rate, prompting that NRAGE may be a molecular indicator for predicting radiation resistance and even the efficacy of radiotherapy for esophageal squamous cell carcinoma

RESUMEN

Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE) is a type II melanoma-associated antigen that plays an essential role in various processes, including cell differentiation and apoptosis. NRAGE has been shown to act as a cancer-related protein, with complex and apparently contradictory functions in a variety of cancers. In the current study, we examined the expression of NRAGE protein in 169 gastric cancer samples. NRAGE upregulation was correlated with advanced TNM stage, local invasion, and poor survival. Importantly, NRAGE could serve as an independent prognostic factor in patients with gastric cancer. We also examined the expression of NRAGE protein in GES-1 normal gastric epithelial cells and in six gastric cancer cell lines. Inhibition of NRAGE expression by transfection with small interfering RNA reduced the proliferation and invasion of MGC-803 and HGC-27 cells, as demonstrated by CCK-8 and Matrigel invasion assays. NRAGE depletion also sensitized HGC-27 and MGC-803 cells to cisplatin, as shown by CCK-8 and Annexin V/propidium iodide analyses. Western blot analysis also showed that NRAGE depletion negatively regulated Bcl-2 and p-ERK and upregulated ZO-1 and p27 expression levels. In conclusion, our results suggest that NRAGE acts as a tumor promoter in gastric cancer by facilitating cancer invasion and chemoresistance, possibly through regulation of p-ERK and Bcl-2.

Asunto(s)

Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/fisiología , Antineoplásicos/farmacología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Cisplatino/farmacología , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas de Neoplasias/fisiología , Pronóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad

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OBJECTIVE: To explore whether neurotrophin receptor-interacting MAGE homolog (NRAGE) is involved in the intestinal ischemia-reperfusion (I/R) and its effect on the apoptosis of intestinal epithelial cells and the expression of occludin protein. METHODS: The level of NRAGE protein after the rat small intestine I/R was detected by immunohistochemical (IHC) In vivo. The level of NRAGE protein and mRNA in IEC-6 cells after hypoxia and reoxygenation were tested by Western blot and RT-PCR respectively in vitro. The IEC-6 cells were divided into four groups, including NRAGE overexpression by lentivirus infection (Lv-NRAGE group), interference (sh-NRAGE group), lentivirus control (Lv-control group), and normal control group without lentivirus infection (NC group). The apoptosis of IEC-6 cells after infection was analyzed by flow cytometry. The level of the tight junction protein occludin was detected by Western blot. RESULTS: The expression of NRAGE were highly increased in intestinal mucosa epithelial cells after I/R (P<0.01). The proteins and mRNA levels of NRAGE were increased after 6 h of hypoxia in IEC-6 cellsin vitro. Compared with the Lv-control group, the early apoptosis rate was raised (P<0.01) and the level of occludin was reduced (P<0.01) in Lv-NRAGE group; while the early apoptosis rate was reduced (P<0.01) and the level of occludin was raised in sh-NRAGE group(P<0.001). CONCLUSION: NRAGE may be involved in intestinal I/R and promote the apoptosis and decrease occludin expression of intestinal epithelial cells.

Asunto(s)

Apoptosis , Células Epiteliales/citología , Proteínas de Neoplasias/metabolismo , Ocludina/metabolismo , Animales , Línea Celular , Mucosa Intestinal , Intestinos/citología , Ratas , Receptores de Factor de Crecimiento Nervioso

RESUMEN

NRAGE has been reported to be overexpressed in cancer cells, especially in lung cancer cells. To determine the role of NRAGE in non-small-cell lung cancer cells, we investigated the effects of NRAGE on autophagy in non-small-cell lung cancer cells. Human A549 and H1299 cells were transfected with NRAGE-specific small-interfering RNA. The Cell Counting Kit-8 and plate clone assay showed that downregulation of NRAGE could induce the proliferation in A549 and H1299 cells. In addition, our data suggested that downregulation of NRAGE enhances autophagosome formation by immunofluorescence. We found that knockdown of NRAGE induced autophagy, together with downregulation of P62 and upregulation of LC3-II protein. Furthermore, to elucidate the mechanism of NRAGE in suppressing autophagy, the protein expressions of AMPK, Ulk1, and Atg13 were assessed. Collectively, these results demonstrate the effective anti-autophagic of NRAGE in non-small-cell lung cancer cells through AMPK/Ulk1/Atg13 autophagy signaling pathways. Therefore, NRAGE could be used as a potential therapeutic target for lung cancer.

Asunto(s)

Proteínas Quinasas Activadas por AMP/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Antígenos de Neoplasias/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Neoplasias/genética , Células A549 , Proteínas Quinasas Activadas por AMP/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/biosíntesis , Proteínas Relacionadas con la Autofagia/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Proteínas de Neoplasias/antagonistas & inhibidores , Fosforilación , ARN Interferente Pequeño , Transducción de Señal

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The Wnt pathway is crucial for animal development, as well as tumor formation. Understanding the regulation of Wnt signaling will help to elucidate the mechanism of the cell cycle, cell differentiation and tumorigenesis. It is generally accepted that in response to Wnt signals, ß-catenin accumulates in the cytoplasm and is imported into the nucleus where it recruits LEF/TCF transcription factors to activate the expression of target genes. In this study, we report that human NRAGE, a neurotrophin receptor p75 (p75NTR) binding protein, markedly suppresses the expression of genes activated by the Wnt pathway. Consistent with this finding, loss of function of NRAGE by RNA interference (RNAi) activates the Wnt pathway. Moreover, NRAGE suppresses the induction of axis duplication by microinjected ß-catenin in Xenopus embryos. To our surprise, NRAGE induces nuclear localization of ß-catenin and increases its DNA binding ability. Further studies reveal that NRAGE leads to the modification of ß-catenin/Arm with O-linked beta-N-acetylglucosamine (O-GlcNAc), and failure of the association between ß-catenin/Arm and pygopus(pygo) protein, which is required for transcriptional activation of Wnt target genes. Therefore, our findings suggest a novel mechanism for regulating Wnt signaling.

Asunto(s)

Acetilglucosamina/metabolismo , Antígenos de Neoplasias/metabolismo , ADN/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Proteínas de Neoplasias/metabolismo , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo , Acilación/fisiología , Proteínas del Dominio Armadillo/metabolismo , Núcleo Celular/metabolismo , Regulación hacia Abajo/fisiología , Células HEK293 , Humanos

RESUMEN

During the course of normal aging, certain populations of nerve growth factor (NGF)-responsive neurons become selectively vulnerable to cell death. Studies using dissociated neurons isolated from neonates have shown that c-Jun N-terminal kinases (JNKs) are important in regulating the survival and neurite outgrowth of NGF-responsive sympathetic neurons. Unlike neonatal neurons, adult sympathetic neurons are not dependent on NGF for their survival. Moreover, the NGF precursor, proNGF, is neurotoxic for aging but not young adult NGF-responsive neurons. Because of these age-related differences, the effects of JNK inhibition on the survival and growth of sympathetic neurons isolated from aged mice were studied. Aged neurons, as well as glia, were found to be dependent on JNK for their growth but not their survival. Conversely, proNGF neurotoxicity was JNK-dependent and mediated by the p75-interacting protein NRAGE, whereas neurite outgrowth was independent of NRAGE. These results have implications for the potential use of JNK inhibitors as therapies for ameliorating age-related neurodegenerative disease.

Asunto(s)

Envejecimiento/genética , Envejecimiento/patología , Procesos de Crecimiento Celular/genética , Supervivencia Celular/genética , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Neuronas/citología , Neuronas/fisiología , Sistema Nervioso Simpático/citología , Animales , Muerte Celular/genética , Muerte Celular/fisiología , Células Cultivadas , Masculino , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Proteínas de Neoplasias/fisiología , Factor de Crecimiento Nervioso/fisiología , Factor de Crecimiento Nervioso/toxicidad , Neuritas/fisiología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/terapia , Precursores de Proteínas/toxicidad , Ratas Sprague-Dawley

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NRAGE, also known as Dlxin-1or MAGE-D1, is a member of type II melanoma-associated antigen (MAGE) and plays an essential role in life activities, including differentiation, apoptosis, and cell cycle. Studies increasingly found that NRAGE is closely related to the tumor events, such as tumor occurrence, invasion, and metastasis. However, complex and contradictory functions of NRAGE in different circumstances are observed, suggesting that NRAGE is unique from other MAGE gene family members. This review summarizes recent findings concerning the structure and biological functions of NRAGE, which may provide a basis for a more comprehensive understanding of and further research on NRAGE.

Asunto(s)

Antígenos de Neoplasias/fisiología , Proteínas de Neoplasias/fisiología , Neoplasias/etiología , Animales , Apoptosis , Carcinogénesis , Ciclo Celular , Diferenciación Celular , Humanos , Neoplasias/patología

RESUMEN

Radiotherapy (RT) is one main method for the treatment of esophageal squamous cell carcinoma (ESCC), and the radioresistance is the predominant cause of patients with local recurrence. The previous results of gene microarray and subsequent verification showed that NRAGE might be involved in radiation resistance of ESCC cells. In this study, we reestablished human esophageal carcinoma radioresistant cell lines TE13R120 and ECA109R60 with gradient dose irradiation as previously reported, respectively. NRAGE expression was high in TE13R120 and ECA109R60 cells and was correlative with ionizing radiation (IR) resistance in clinic. However, the radiosensitivity of TE13R120 cells had a remarkable increase detected by colony formation assays after siRNA against NRAGE (siNRG) transfection into TE13R120 cells. Compared with TE13 cells, an increasing number of TE13R120 cells with NRAGE overexpression in S phase and a lower ratio in G2/M were observed by flow cytometry method (FCM). Intriguingly, the above changes were partially reversed in TE13R120 cells treated with siNRG. More importantly, the ectopic subcellular localization of NRAGE mediated nuclear translocation of ß-catenin which may be one reason of IR resistance of esophageal carcinoma cell. These data indicate that NRAGE extremely may be a pivotal factor involved in Wnt/ß-catenin signal pathway, mediating nuclear translocation of ß-catenin and then facilitating the formation of radioresistance of ESCC.

Asunto(s)

Antígenos de Neoplasias/genética , Neoplasias Esofágicas/genética , Proteínas de Neoplasias/genética , Tolerancia a Radiación/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Ciclo Celular/genética , Línea Celular Tumoral , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago , Femenino , Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , ARN Interferente Pequeño/genética , Radiación Ionizante , Dosificación Radioterapéutica , Vía de Señalización Wnt/genética , Adulto Joven , beta Catenina/genética

RESUMEN

OBJECTIVES: Neurotrophin receptor-mediated melanoma antigen-encoding gene homology (NRAGE) is an important regulator of proliferation, cell cycle arrest and apoptosis. Our previous study showed that NRAGE is an important regulator of proliferation and odontogenic differentiation of mouse dental pulp cells. This study aimed to investigate the effects of NRAGE on the cell cycle and apoptosis on human dental pulp cells (hDPCs) and MDPC-23. MATERIALS AND METHODS: Cells were infected by recombinant lentivirus to stably knockdown the expression of NRAGE, then the biological effects of NRAGE on the MDPC-23 was detected. The cell cycle distributions and apoptosis of hDPCs and MCPC-23 were performed by flow cytometric analysis. Simultaneously, the cell cycle and apoptosis were also detected after cells treated with IKK inhibitor. RESULTS: The mRNA and protein levels of NRAGE decreased significantly after infected by recombinant lentivirus. Knockdown of NRAGE inhibited the apoptosis in hDPCs and MCPC-23. Knockdown of NRAGE show significantly G0G1 arrest in hDPCs, while no significantly difference in MDPC-23. Meanwhile, Knockdown of NRAGE activated the NF-κB signaling pathway. After treated with IKK inhibitor, the effect of NRAGE knockdown on apoptosis was reversed in both hDPCs and MDPC-23. CONCLUSION: NRAGE is a potent regulator for cell cycle and apoptosis of hDPCs. Knockdown of NRAGE inhibited apoptosis of hDPCs and MDPC-23 through the NF-κB signaling pathway.