Transmembrane p24 Trafficking Protein 2 Regulates Inflammation Through the TLR4/NF-κB Signaling Pathway in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Longhua Feng ◽  
Pengjiang Cheng ◽  
Zhengyun Feng ◽  
Xiaoyu Zhang
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Inflammatory Factors ◽  
Normal Tissues ◽  
Kaplan Meier ◽  
New Strategy

Abstract Background: To investigate the role of transmembrane p24 trafficking protein 2 (TMED2) in lung adenocarcinoma (LUAD) and determine whether TMED2 knockdown could inhibit LUAD in vitro and in vivo.Methods: TIMER2.0, Kaplan-Meier plotter, gene set enrichment analysis (GSEA), Target Gene, and pan-cancer systems were used to predict the potential function of TMED2. Western blotting and immunohistochemistry were performed to analyze TMED2 expression in different tissues or cell lines. The proliferation, development, and apoptosis of LUAD were observed using a lentivirus-mediated TMED2 knockdown. Bioinformatics and western blot analysis of TMED2 against inflammation via the TLR4/NF-κB signaling pathway were conducted. Results: TMED2 expression in LUAD tumor tissues was higher than that in normal tissues and positively correlated with poor survival in lung cancer and negatively correlated with apoptosis in LUAD. The expression of TMED2 was higher in tumors or HCC827 cells. TMED2 knockdown inhibited LUAD development in vitro and in vivo and increased the levels of inflammatory factors via the TLR4/NF-κB signaling pathway. TMED2 was correlated with TME, immune score, TME-associated immune cells, their target markers, and some mechanisms and pathways, as determined using the TIMER2.0, GO, and KEGG assays.Conclusions: TMED2 may regulate inflammation in LUAD through the TLR4/NF-κB signaling pathway, and enhance the proliferation, development, and prognosis of LUAD by regulating inflammation, which provide a new strategy for treating LUAD by regulating inflammation.

scholarly journals DPYSL2 as potential diagnostic and prognostic biomarker linked to immune infiltration in lung adenocarcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yang-Jie Wu ◽  
Ai-Tao Nai ◽  
Gui-Cheng He ◽  
Fei Xiao ◽  
Zhi-Min Li ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Roc Curve ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
List Type ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Normal Tissues ◽  
Kaplan Meier ◽  
Kaplan Meier Plotter

Abstract Background Dihydropyrimidinase like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored. Methods Herein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan–Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated. Results In this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan–Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cells, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2. Conclusions In summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target. Highlights Expression of DPYSL2 was considerably lower in LUAD than in normal tissues. Investigation of multiple databases showed a high diagnostic value of DPYSL2 in LUAD. DPYSL2 can independently predict the LUAD outcomes. Immune-related mechanisms may be potential ways for DPYSL2 to play a role in LUAD.

scholarly journals ANXA1 Induces Oxaliplatin Resistance of Gastric Cancer through Autophagy by Targeting PI3K/AKT/mTOR

2021 ◽  
Author(s):  
Jun Ren ◽  
Qing Zhi Hu ◽  
Ming Geng Niu ◽  
Jie Xia ◽  
Xing Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Western Blot ◽  
Signaling Pathway ◽  
Enrichment Analysis ◽  
Mtor Signaling ◽  
Gene Set Enrichment Analysis ◽  
Rna Seq ◽  
Mtor Signaling Pathway

Abstract Background: Resistance to oxaliplatin (OXA) is a major cause of recurrence in gastric cancer (GC) patients. ANXA1 has been found to participate in the regulation of diverse cellular functions in a variety of cell types including anti-inflammatory processes. We aimed to investigate the role of ANXA1 in autophagy and chemoresistance of GC cells. Methods: To identify the genes that regulate oxaliplatin resistance, we used RNA-seq to profile gene expression within oxaliplatin resistant GC and parental cells. Immunohistochemical and RT-qPCR was performed to detect ANXA1 expression in tissues of 2 cohorts of GC patients who received OXA-based chemotherapy. The chemoresistant effects of ANXA1 were assessed by cell viability, apoptosis, and autophagy assays. The effects of ANXA1 on autophagy were assessed by mRFP-GFP-LC3 and western blot. Gene set enrichment analysis (GSEA) and western blot was performed to detect the activity of PI3K/AKT/mTOR signaling under the regulation of ANXA1.Results: Based on RNA-seq profiling, ANXA1 was selected as a candidate that was upregulated in oxaliplatin resistant GC cells. Furthermore, we discovered that ANXA1 is upregulated in chemo-resistant GC tissues. Knockdown of ANXA1, via inhibiting autophagy, enhanced the sensitivity of OXA-resistant GC cells to OXA in vitro and in vivo. Mechanically, we identified that PI3K/AKT/mTOR signaling pathway was activated in the ANXA1 stably knockdown AGS/OXA cells, which leads to the down-regulation of autophagy.Conclusions: ANXA1 functions as a chemoresistant gene in GC cells by targeting the PI3K/AKT/mTOR signaling pathway and might be a prognostic predictor for GC patients who receive OXA-based chemotherapy.

scholarly journals Downregulation of NEDD4L by EGFR Signaling Promotes the Development of Lung Adenocarcinoma

2021 ◽  
Author(s):  
Guoyin Li ◽  
Zewen Song ◽  
Changjing Wu ◽  
XiaoYan Li ◽  
Liping Zhao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Data Sets ◽  
Egfr Signaling ◽  
Gene Set Enrichment ◽  
Mtorc1 Pathway ◽  
Cumulative Evidence

Abstract Cumulative evidence indicates that the abnormal regulation of the NEDD4 family of E3-ubiquitin ligases participates in the tumorigenesis and development of cancer. However, their role in lung adenocarcinoma (LUAD) remains unclear. This study comprehensively analyzed the NEDD4 family in LUAD data sets from public databases and found only NEDD4L was associated with the overall survival of LUAD patients. Gene set enrichment analysis (GSEA) indicated that NEDD4L might be involved in the regulation of mTORC1 pathway. Both cytological and clinical assays showed that NEDD4L inhibited the activity of the mTOR signaling pathway. In vivo and in vitro experiments showed that NEDD4L could significantly inhibit the proliferation of LUAD cells. In addition, this study also found that the expression of NEDD4L was regulated by EGFR signaling. These findings firstly revealed that NEDD4L mediates an interplay between EGFR and mTOR pathways in LUAD, and suggest that NEDD4L held great potential as a novel biomarker and therapeutic target for LUAD.

scholarly journals Downregulation of NEDD4L by EGFR Signaling Promotes the Development of Lung Adenocarcinoma

2021 ◽  
Author(s):  
Guoyin Li ◽  
Zewen Song ◽  
Changjing Wu ◽  
XiaoYan Li ◽  
Liping Zhao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Data Sets ◽  
Egfr Signaling ◽  
Gene Set Enrichment ◽  
Mtorc1 Pathway ◽  
Cumulative Evidence

Abstract Cumulative evidence indicates that the abnormal regulation of the NEDD4 family of E3-ubiquitin ligases participates in the tumorigenesis and development of cancer. However, their role in lung adenocarcinoma (LUAD) remains unclear. This study comprehensively analyzed the NEDD4 family in LUAD data sets from public databases and found only NEDD4L was associated with the overall survival of LUAD patients. Gene set enrichment analysis (GSEA) indicated that NEDD4L might be involved in the regulation of mTORC1 pathway. Both cytological and clinical assays showed that NEDD4L inhibited the activity of the mTOR signaling pathway. In vivo and in vitro experiments showed that NEDD4L could significantly inhibit the proliferation of LUAD cells. In addition, this study also found that the expression of NEDD4L was regulated by EGFR signaling. These findings firstly revealed that NEDD4L mediates an interplay between EGFR and mTOR pathways in LUAD, and suggest that NEDD4L held great potential as a novel biomarker and therapeutic target for LUAD.

scholarly journals Interrogation of gender disparity uncovers androgen receptor as the transcriptional activator for oncogenic miR-125b in gastric cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ben Liu ◽  
Meng Zhou ◽  
Xiangchun Li ◽  
Xining Zhang ◽  
Qinghua Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Androgen Receptor ◽  
Signaling Pathway ◽  
Gender Bias ◽  
Gender Disparity ◽  
Gene Set Enrichment Analysis ◽  
Cancer Type ◽  
Female Patients

AbstractThere is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.

scholarly journals TNF-α Triggers RIP1/FADD/Caspase-8-Mediated Apoptosis of Astrocytes and RIP3/MLKL-Mediated Necroptosis of Neurons Induced by Angiostrongylus cantonensis Infection

2021 ◽  
Author(s):  
Hongli Zhou ◽  
Minyu Zhou ◽  
Yue Hu ◽  
Yanin Limpanon ◽  
Yubin Ma ◽  
...  
Keyword(s):  
Cell Death ◽  
Enrichment Analysis ◽  
Angiostrongylus Cantonensis ◽  
Gene Set Enrichment Analysis ◽  
Caspase 8 ◽  
Cns Injury ◽  
Vitro Assay ◽  
Tnf Α

AbstractAngiostrongylus cantonensis (AC) can cause severe eosinophilic meningitis or encephalitis in non-permissive hosts accompanied by apoptosis and necroptosis of brain cells. However, the explicit underlying molecular basis of apoptosis and necroptosis upon AC infection has not yet been elucidated. To determine the specific pathways of apoptosis and necroptosis upon AC infection, gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) analysis for gene expression microarray (accession number: GSE159486) of mouse brain infected by AC revealed that TNF-α likely played a central role in the apoptosis and necroptosis in the context of AC infection, which was further confirmed via an in vivo rescue assay after treating with TNF-α inhibitor. The signalling axes involved in apoptosis and necroptosis were investigated via immunoprecipitation and immunoblotting. Immunofluorescence was used to identify the specific cells that underwent apoptosis or necroptosis. The results showed that TNF-α induced apoptosis of astrocytes through the RIP1/FADD/Caspase-8 axis and induced necroptosis of neurons by the RIP3/MLKL signalling pathway. In addition, in vitro assay revealed that TNF-α secretion by microglia increased upon LSA stimulation and caused necroptosis of neurons. The present study provided the first evidence that TNF-α was secreted by microglia stimulated by AC infection, which caused cell death via parallel pathways of astrocyte apoptosis (mediated by the RIP1/FADD/caspase-8 axis) and neuron necroptosis (driven by the RIP3/MLKL complex). Our research comprehensively elucidated the mechanism of cell death after AC infection and provided new insight into targeting TNF-α signalling as a therapeutic strategy for CNS injury.

scholarly journals Benchmarking substrate-based kinase activity inference using phosphoproteomic data

2016 ◽  
Author(s):  
Claudia Hernandez-Armenta ◽  
David Ochoa ◽  
Emanuel Gonçalves ◽  
Julio Saez-Rodriguez ◽  
Pedro Beltrao
Keyword(s):  
Kinase Activity ◽  
Multiple Linear Regression Model ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Target Sequence ◽  
Sequence Specificity ◽  
Gold Standard Dataset ◽  
Kolmogorov Smirnov

AbstractMotivationPhosphoproteomic experiments are increasingly used to study the changes in signalling occurring across different conditions. It has been proposed that changes in phosphorylation of kinase target sites can be used to infer when a kinase activity is under regulation. However, these approaches have not yet been benchmarked due to a lack of appropriate benchmarking strategies.ResultsWe curated public phosphoproteomic experiments to identify a gold standard dataset containing a total of 184 kinase-condition pairs where regulation is expected to occur. A list of kinase substrates was compiled and used to estimate changes in kinase activities using the following methods: Z-test, Kolmogorov Smirnov test, Wilcoxon rank sum test, gene set enrichment analysis (GSEA), and a multiple linear regression model (MLR). We also tested weighted variants of the Z-test, and GSEA that include information on kinase sequence specificity as proxy for affinity. Finally, we tested how the number of known substrates and the type of evidence (in vivo, in vitro or in silico) supporting these influence the predictions.ConclusionsMost models performed well with the Z-test and the GSEA performing best as determined by the area under the ROc curve (Mean AUC=0.722). Weighting kinase targets by the kinase target sequence preference improves the results only marginally. However, the number of known substrates and the evidence supporting the interactions has a strong effect on the predictions.

scholarly journals Apelin Over-Expression Promotes Proliferation and Angiogenesis of Gastric Cancer Cells

2021 ◽  
Author(s):  
Li-Jun Tian ◽  
Hong-Zhi Liu ◽  
Qiang Zhang ◽  
Dian-Zhong Geng ◽  
Jing Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cox Regression ◽  
Gastric Cancer Cells ◽  
Over Expression ◽  
Normal Tissues

Abstract Background: Apelin is a recently identified endogenous ligand associated with proliferation and angiogenesis of several cancers. However, only few studies have reported on the functions and the role of apelin in gastric cancer (GC). Therefore, in the present study, we investigated the association and the mechanisms underlying Apelin expression and proliferation of GC cells both in vitro and in vivo.Methods: We enrolled 178 postoperative care GC patients to investigate clinicopathological and immunohistochemical factors associated with Apelin expression. The relationship between Survival of patients and apelin expression was evaluated using Kaplan-Meier method and Cox regression analyses. The expression of apelin mRNA and its proteins in GC tissues and cell lines were analyzed using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), western blot and ELISA. The role and mechanisms underlying regulation of Apelin expression in human GC cells were evaluated through several in vitro and in vivo experiments. Results: Apelin was over expressed in human GC cells, relative to adjacent normal tissues. The over expression of apelin was associated with vessel invasion (P <0.01), lymph node metastasis (P <0.01), late-staged tumor (T) (P <0.05), worse pathological type (P <0.05), nerve invasion (P <0.05). In addition, expression of apelin strongly and positively correlated with that of vascular endothelial growth factor (VEGF). Over-expression of apelin promoted proliferation and invasion of MGC-803 cell via the ERK/Cyclin D1/MMP-9 signaling pathway. Apelin over-expression also promoted angiogenesis of GC cells, accelerating growth of subcutaneous xenograft of the cancer cells in vivo.Conclusions: Over-expression of apelin promotes proliferation and metastasis of GC cells via the ERK/Cyclin D1/MMP-9 signaling pathway and is associated with adverse events of the cancer. Consequently, apelin is a potential therapeutic target for human GC.

scholarly journals Norepinephrine exposure restrains endometrial decidualization in early pregnancy

2021 ◽  
Author(s):  
Jiju Wang ◽  
Yuhui Tang ◽  
Songcun Wang ◽  
Liyuan Cui ◽  
Da-Jin Li ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Adrenergic Receptor ◽  
Enrichment Analysis ◽  
Normal Pregnancy ◽  
Receptor Expression ◽  
Gene Set Enrichment Analysis ◽  
Endometrial Stromal Cells ◽  
Significant Enrichment

Previous studies have focused on the role of norepinephrine on arrhythmias, generalized anxiety disorder, and cancer. This study aimed to investigate the effect of norepinephrine on endometrial decidualization. Artificial decidualization and norepinephrine-treated mice were established in vivo. In vitro, human endometrial stromal cells were treated with MPA and cAMP to induce decidualization. Decidual markers and important signaling molecules during decidualization were detected using quantitative real-time polymerase chain reaction and Western blot. RNA sequencing was performed to determine related signaling pathways. Exposure of excess norepinephrine significantly restricted the induced expression of decidualized markers Dtprp, BMP2, WNT4, and Hand2 in mice. In vitro, 10 µM norepinephrine markedly downregulated the expressions of prolactin, IGFBP1, and PLZF, which are the specifical markers of decidual stromal cells during decidualization. The gene set enrichment analysis showed that a significant enrichment in neuroactive ligand–receptor interactions of norepinephrine treatment group. The α1b-adrenergic receptor expression was upregulated by norepinephrine. Interestingly, norepinephrine did not inhibit the expression of IGFBP1 in endometrial stromal cells after silencing α1b-adrenergic receptor, while significantly suppressed the induced decidualization with overexpression of α1b-adrenergic receptor. When α1b-adrenergic receptor was activated, endometrial p-PKC was significantly increased under post-treatment with norepinephrine in vivo and in vitro. In addition, norepinephrine treatment inhibited embryo and fetal development using a normal pregnancy model. Therefore, norepinephrine exposure inhibited endometrial decidualization through the activation of the PKC signaling pathway by upregulating α1b-adrenergic receptor. Our study could explain some female reproductive problems due to stress and provide some novel strategies for this disorder.

scholarly journals Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Guo Zu ◽  
Jing Guo ◽  
Ningwei Che ◽  
Tingting Zhou ◽  
Xiangwen Zhang
Keyword(s):  
Signaling Pathway ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Ginsenoside Rg1 ◽  
Intestinal Ischemia Reperfusion

Abstract Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury.

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