NDRG2 combined with EGFR improved its prognostic value for lung adenocarcinoma

Abstract Background N-Myc downstream-regulated gene2 (NDRG2) plays an important role in lung adenocarcinoma (LUAD). Epidermal growth factor receptor (EGFR) mutation has significantly improved prognosis in patients with adenocarcinoma. We aimed to elucidate the clinical value of NDRG2/EGFR as a prediction of prognosis in patients with lung adenocarcinoma.Materials and Methods Immunohistochemistry and western blot analysis were conducted to detect the expression of NDRG2 protein. Association between NDRG2/EGFR expression and clinicopathological parameters of the patients were examined. Serum Carcinoembryonic antigen (CEA) level was examined prior to treatment in patients with LUAD. Patients’ survival rate was assessed by Kaplan–Meier. Candidates for independent prognostic biomarkers were analyzed using a COX proportional hazard model.Results NDRG2 levels were significantly decreased in patients with lung adenocarcinoma. NDRG2 levels were positively correlated with CEA and EGFR. Advanced stages were significantly associated with low expression of NDRG2. Patients with NDRG2-high combined with EGFR-positive expression had the best prognosis during the 5-year follow-up period. Meanwhile, COX regression analysis showed that the conjoined expressions of NDRG2-low/EGFR-positive, NDRG2-high/EGFR-positive and vascular invasion were independent prognostic indicators for lung adenocarcinoma.Conclusion NDRG2 is of more prognosis value as the biomarker for lung adenocarcinoma when analyzed combined with the EGFR expression.

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Prognostic significance of NDRG2 combined with EGFR patients with lung adenocarcinoma

10.21203/rs.2.14181/v2 ◽

2019 ◽

Author(s):

Bo Yang ◽

Xiao-Ping Li ◽

Hong-Gang Zhou ◽

Tao Jiang ◽

Ting Xiao ◽

...

Keyword(s):

Regression Analysis ◽

Lung Adenocarcinoma ◽

Prognostic Value ◽

Cox Regression ◽

Prognostic Significance ◽

Growth Factor Receptor ◽

Clinicopathological Characteristics ◽

Expression Level ◽

Cox Regression Analysis ◽

Egfr Expression

Abstract Background: N-myc downstream-regulated gene 2 (NDRG2) plays a substantial role in lung adenocarcinoma (LUAD). Epidermal growth factor receptor (EGFR) mutation could significantly improve prognosis in patients with LUAD. In this study, we aimed to elucidate the prognostic value of NDRG2/EGFR in patients with LUAD. Methods: Immunohistochemistry, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) were conducted to detect the expression levels of NDRG2 protein. Association between NDRG2/EGFR expression and clinicopathological characteristics of patients with LUAD was examined as well. Serum level of carcinoembryonic antigen (CEA) was tested prior to treatment of patients with LUAD. Patients’ overall survival was assessed by Kaplan–Meier method. Multivariate Cox regression analysis was carried out to investigate the effects of patients’ demographic characteristics on OS. Results: The expression level of NDRG2 was significantly decreased in patients with LUAD. The expression level of NDRG2 was positively correlated with levels of CEA and EGFR. Advanced stages were significantly associated with low expression level of NDRG2. We found that patients in NDRG2-high/EGFR(+) group had the best outcome, while patients in NDRG2-low/EGFR(-) group had the worst. Meanwhile, Cox regression analysis showed that NDRG2-low/EGFR(+), NDRG2-high/EGFR(+), and vascular invasion were independent prognostic factors of LUAD. Conclusion: The significant prognostic value of NDRG2/EGFR should be highly considered in patients with LUAD.

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Prognostic significance of NDRG2 combined with EGFR patients with lung adenocarcinoma

10.21203/rs.2.14181/v3 ◽

2020 ◽

Author(s):

Bo Yang ◽

Xiao-Ping Li ◽

Hong-Gang Zhou ◽

Tao Jiang ◽

Ting Xiao ◽

...

Keyword(s):

Overall Survival ◽

Regression Analysis ◽

Lung Adenocarcinoma ◽

Cox Regression ◽

Prognostic Significance ◽

Growth Factor Receptor ◽

Serum Levels ◽

Clinicopathological Characteristics ◽

Cox Regression Analysis ◽

Egfr Expression

Abstract Background: N-myc downstream-regulated gene 2 (NDRG2) plays a substantial role in lung adenocarcinoma (LUAD). Epidermal growth factor receptor (EGFR) mutation could significantly improve prognosis in patients with LUAD. In this study, we aimed to elucidate the prognostic value of NDRG2/EGFR in patients with LUAD. Methods: Immunohistochemistry, western blotting, and real-time polymerase chain reaction (RT-PCR) were conducted to detect the expression levels of NDRG2 protein. Associations between NDRG2/EGFR expression and clinicopathological characteristics of patients with LUAD were examined as well. Serum levels of carcinoembryonic antigen (CEA) were tested prior to treatments. Patients’ overall survival (OS) was assessed by the Kaplan-Meier method. Multivariate Cox regression analysis was carried out to investigate the effects of patients’ demographic characteristics on overall survival . Results: The expression of NDRG2 was significantly decreased in patients with LUAD. The expression of NDRG2 was positively correlated with the levels of CEA and EGFR. Advanced stages were significantly associated with low expression of NDRG2. We found that the patients in the NDRG2-high/EGFR(+) group had the best outcomes, while the patients in the NDRG2-low/EGFR(-) group had the worst outcomes. Cox regression analysis showed that NDRG2-low/EGFR(+), NDRG2-high/EGFR(+), and vascular invasion were independent prognostic factors of LUAD. Conclusion: NDRG2 and EGFR should be considered in patients with LUAD.

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Upregulation of GNPNAT1 Predicts Poor Prognosis and Correlates With Immune Infiltration in Lung Adenocarcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.605754 ◽

2021 ◽

Vol 8 ◽

Author(s):

Wenting Liu ◽

Kaiting Jiang ◽

Jingya Wang ◽

Ting Mei ◽

Min Zhao ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Signaling Pathways ◽

Poor Prognosis ◽

Cox Regression ◽

Clinical Stage ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Clinical Value ◽

Cox Regression Analysis ◽

Normal Tissues

BackgroundGlucosamine 6-phosphate N-acetyltransferase (GNPNAT1) is a key enzyme in the hexosamine biosynthetic pathway (HBP), which functions as promoting proliferation in some tumors, yet its potential biological function and mechanism in lung adenocarcinoma (LUAD) have not been explored.MethodsThe mRNA differential expression of GNPNAT1 in LUAD and normal tissues was analyzed using the Cancer Genome Atlas (TCGA) database and validated by real-time PCR. The clinical value of GNPNAT1 in LUAD was investigated based on the data from the TCGA database. Then, immunohistochemistry (IHC) of GNPNAT1 was applied to verify the expression and clinical significance in LUAD from the protein level. The relationship between GNPNAT1 and epigenetics was explored using the cBioPortal database, and the miRNAs regulating GNPNAT1 were found using the miRNA database. The association between GNPNAT1 expression and tumor-infiltrating immune cells in LUAD was observed through the Tumor IMmune Estimation Resource (TIMER). Finally, Gene set enrichment analysis (GSEA) was used to explore the biological signaling pathways involved in GNPNAT1 in LUAD.ResultsGNPNAT1 was upregulated in LUAD compared with normal tissues, which was verified through qRT-PCR in different cell lines (P < 0.05), and associated with patients’ clinical stage, tumor size, and lymphatic metastasis status (all P < 0.01). Kaplan–Meier (KM) analysis suggested that patients with upregulated GNPNAT1 had a relatively poor prognosis (P < 0.0001). Furthermore, multivariate Cox regression analysis indicated that GNPNAT1 was an independent prognostic factor for LUAD (OS, TCGA dataset: HR = 1.028, 95% CI: 1.013–1.044, P < 0.001; OS, validation set: HR = 1.313, 95% CI: 1.130–1.526, P < 0.001). GNPNAT1 overexpression was correlated with DNA copy amplification (P < 0.0001), low DNA methylation (R = −0.52, P < 0.0001), and downregulation of hsa-miR-30d-3p (R = −0.17, P < 0.001). GNPNAT1 expression was linked to B cells (R = −0.304, P < 0.0001), CD4+T cells (R = −0.218, P < 0.0001), and dendritic cells (R = −0.137, P = 0.002). Eventually, GSEA showed that the signaling pathways of the cell cycle, ubiquitin-mediated proteolysis, mismatch repair and p53 were enriched in the GNPNAT1 overexpression group.ConclusionGNPNAT1 may be a potential prognostic biomarker and novel target for intervention in LUAD.

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IL-11RA is a Prognostic Biomarker and Correlated with Immune Infiltration in Lung Adenocarcinoma

10.21203/rs.3.rs-673757/v1 ◽

2021 ◽

Author(s):

Aitao Nai ◽

SHOAIB BASHIR ◽

Ling Jin ◽

Zirui He ◽

Shuwen Zeng ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Cox Regression ◽

Progression Free Survival ◽

Clinicopathological Parameters ◽

Free Survival ◽

Cox Regression Analysis ◽

Immune Infiltration ◽

Potential Biomarker

Abstract Background: Interleukin-11 receptor subunit alpha (IL-11RA) contributes to multiple biological processes in various tumors. However, the role of IL-11RA in Lung adenocarcinoma (LUAD) is still undetermined. The study aims to explore the role of IL-11RA in LUAD via an integrated bioinformatics analysis. Methods: TIMER, GEPIA, TCGA and HPA databases analysis were used to detect IL-11RA expression. UALCAN database was used to analysis the correlation between IL-11RA expression and clinicopathological parameters of LUAD. Kaplan-Meier Plotter, TCGA and GEO databases were used to analysis overall survival (OS) and progression-free survival (PFS) of the LUAD patients. Univariate Cox regression analysis was used to assess the prognostic value of IL-11RA in different clinical characteristics. GSEA, and TIMER were used to investigate the relationship between IL-11RA and immune infiltration.Results: The expression of IL-11RA was down-regulated in LUAD tissues. Furthermore, IL-11RA expression was closely associated with clinical stage, lymph node stage and smoking habits. The patients with lower IL-11RA expression had poorer overall survival (OS) and progression-free survival (PFS). Lower IL-11RA expression was significantly associated with its hypermethylation, and the hypermethylation of CpG site at cg14609668 and cg21504624 was obviously correlated with poorer OS. Then, we found that IL-11RA may play an important role in LUAD progression and immune regulations. Notably, High expression of IL-11RA may suppress the progression of LUAD through inhibiting cell proliferation and immune cell infiltration, especially in B cells, CD4+ T cells, and Dendritic Cell. Conclusions: Decreased IL-11RA expression correlates with poor prognosis and immune infiltration in LUAD. Our work highlights IL-11RA might be a potential biomarker for prognosis and provide a new therapeutic target for LUAD patients.

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Establishment of a 5 DNA Methylation Site Prognostic Signature Associated with N6-Methyladenosine in Lung Adenocarcinoma

10.21203/rs.3.rs-1071199/v1 ◽

2021 ◽

Author(s):

Liqiang Yuan ◽

Wei Jiang ◽

Zhanyu Xu ◽

Kung Deng ◽

Yu Sun ◽

...

Keyword(s):

Dna Methylation ◽

Lung Adenocarcinoma ◽

Cox Regression ◽

Clinicopathological Parameters ◽

Main Body ◽

Methylation Site ◽

Cox Regression Analysis ◽

Site Model ◽

Kaplan Meier ◽

Cox Analysis

Abstract Background: There is a high incidence of lung adenocarcinoma (LUAD). Even with surgery, targeted therapy and immunotherapy, the survival rate of LUAD patients is still low. N6-methyladenosine (m6A) and DNA methylation markers can help with the diagnosis and treatment of LUAD patients. Therefore, it is necessary to identify a novel m6A-related DNA methylation sites signature to predict the survival of patients with LUAD. Methods: In this study, we screened 15 m6A-related genes and their 217 methylation sites. RNA sequencing data of 15 genes and the clinicopathological parameters of TCGA-LUAD were obtained from the TCGA database (http://cancergenome.nih.gov/). The LUAD-DNA CpG site information was obtained from the Illumina Human Methylation 450 BeadChip (Illumina, San Diego, CA, United States). The methylation sites related to prognosis were screened using univariate COX analysis, and the independent predictors of LUAD patients were identified using multivariate COX analysis of least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Finally, a model with 5 methylation sites as the main body to predict the prognosis of OS in patients with LUAD was obtained. According to the risk grouping of the prediction model, Kaplan-Meier curve and the receiver operating characteristic (ROC) curve were performed in the test and training sets to assess the predicted capacity of the model. In addition, a nomogram constructed by combining the risk score of methylation group and other related clinicopathological factors to verify the reliability of our model.Results: We constructed a m6A-related 5-DNA methylation site model to predict OS in LUAD patients. According to the results of the Kaplan-Meier curve, both the test set and the training set, the high-risk group showed a worse prognosis. The AUCs of the 5 DNA methylation signature at 1, 5 and 10 years in test datasets were 0.730, 0.649 and 0.726, respectively, and 0.679, 0.656 and 0.732 in training datasets. Finally, we constructed a nomogram to further verify the reliability of the model.Conclusion: In this study, we analyzed the methylation sites of m6A-related genes and established a m6A-related 5-DNA methylation site model to predict OS in LUAD patients.

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Genomics and Prognosis Analysis of N6-Methyladenosine Regulators in Lung Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.746666 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yanpin Ma ◽

Huping Zhang

Keyword(s):

Lung Adenocarcinoma ◽

Signaling Pathways ◽

Tumor Immunity ◽

Risk Score ◽

Clustering Analysis ◽

Cox Regression ◽

Expression Profiles ◽

Prognostic Indicators ◽

Consensus Clustering ◽

Cox Regression Analysis

Objective: N6-methyladenosine (m6A) modification is involved in modulating various biological processes in human cancers. But the implication of m6A modification in lung adenocarcinoma (LUAD) is still unclear. Hence, this study conducted a comprehensive analysis of the expression and clinical implication of m6A regulators in LUAD.Methods: Consensus clustering analysis of 502 LUAD samples in the TCGA dataset was presented based on the expression profiles of 20 m6A regulators using ConsensusClusterPlus package. Overall survival (OS), activation of signaling pathways and tumor immunity (immune/stromal score, tumor purity, expression of HLA and immune checkpoints, and immune cell infiltration) were compared between m6A modification patterns. The m6A-related genes between patterns were identified and prognostic m6A-related genes were imported into LASSO-cox regression analysis. The m6A risk score was developed and its prognostic implication was evaluated and externally verified in the GSE30219 and GSE72094 dataset. Furthermore, a nomogram that contained independent prognostic indicators was established, followed by external verification.Results: Two m6A modification patterns were clustered across LUAD based on the expression similarity of the m6A regulators via consensus clustering analysis, with distinct OS, activation of signaling pathways and tumor immunity. Totally, 213 m6A-related genes that were identified by comparing two patterns were significantly related to LUAD prognosis. By LASSO method, we constructed the m6A risk score that was a reliable and independent prognostic factor for LUAD. Patients with low m6A risk score displayed a prominent survival advantage. After incorporating independent clinical features, we developed the prognostic nomogram that exhibited high predictive accuracy and the best clinical net benefit for OS.Conclusion: Collectively, our study may provide a clinically useful tool for precise prognostic management and optimization of immunotherapeutic strategies for LUAD patients.

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Comprehensive analysis of prognostic biomarkers in lung adenocarcinoma based on aberrant lncRNA–miRNA–mRNA networks and Cox regression models

Bioscience Reports ◽

10.1042/bsr20191554 ◽

2020 ◽

Vol 40 (1) ◽

Cited By ~ 3

Author(s):

Yan Yao ◽

Tingting Zhang ◽

Lingyu Qi ◽

Ruijuan Liu ◽

Gongxi Liu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Prediction Models ◽

Cox Regression ◽

Prognostic Index ◽

The Cancer Genome Atlas ◽

Prognostic Biomarkers ◽

Prognostic Indicators ◽

Cox Regression Analysis ◽

Cerna Network ◽

A Genome

Abstract Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, and its underlying mechanism remains unclear. Accumulating evidence has highlighted that long non-coding RNA (lncRNA) acts as competitive endogenous RNA (ceRNA) and plays an important role in the occurrence and development of LUAD. Here, we comprehensively analyzed and provided an overview of the lncRNAs, miRNAs, and mRNAs associated with LUAD from The Cancer Genome Atlas (TCGA) database. Then, differentially expressed lncRNAs (DElncRNA), miRNAs (DEmiRNA), and mRNAs (DEmRNA) were used to construct a lncRNA–miRNA–mRNA regulatory network according to interaction information from miRcode, TargetScan, miRTarBase, and miRDB. Finally, the RNAs of the network were analyzed for survival and submitted for Cox regression analysis to construct prognostic indicators. A total of 1123 DElncRNAs, 95 DEmiRNAs, and 2296 DEmRNAs were identified (|log2FoldChange| (FC) > 2 and false discovery rate (FDR) or adjusted P value < 0.01). The ceRNA network was established based on this and included 102 lncRNAs, 19 miRNAs, and 33 mRNAs. The DEmRNAs in the ceRNA network were found to be enriched in various cancer-related biological processes and pathways. We detected 22 lncRNAs, 12 mRNAs, and 1 miRNA in the ceRNA network that were significantly associated with the overall survival of patients with LUAD (P < 0.05). We established three prognostic prediction models and calculated the area under the 1,3,5-year curve (AUC) values of lncRNA, mRNA, and miRNA, respectively. Among them, the prognostic index (PI) of lncRNA showed good predictive ability which was 0.737, 0.702 and 0.671 respectively, and eight lncRNAs can be used as candidate prognostic biomarkers for LUAD. In conclusion, our study provides a new perspective on the prognosis and diagnosis of LUAD on a genome-wide basis, and develops independent prognostic biomarkers for LUAD.

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Upregulation of Serum lncRNA DLEU1 Predicts Progression of Premalignant Endometrial Lesion and Unfavorable Clinical Outcome of Endometrial Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533033820965589 ◽

2020 ◽

Vol 19 ◽

pp. 153303382096558

Author(s):

Lixia Shan ◽

Tao Zhao ◽

Yu Wang

Keyword(s):

Endometrial Cancer ◽

Endometrial Hyperplasia ◽

Cox Regression ◽

Quantitative Polymerase Chain Reaction ◽

Critical Role ◽

Disease Free Survival ◽

Lymphocytic Leukemia ◽

Healthy Controls ◽

Clinical Value ◽

Cox Regression Analysis

Objective: Long non-coding RNAs (lncRNAs) play a critical role in tumorigenesis. Upregulation of lncRNA deleted in lymphocytic leukemia 1 (DLEU1) has been reported in endometrial cancer (EC) tissues. This prospective study aimed to determine the potential clinical significance of serum lncRNA DLEU1 in EC. Methods: The serum lncRNA DLEU1 level was detected in EC patients, patients with endometrial hyperplasia and healthy controls by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Then its clinical value in EC was further evaluated. Results: Our results demonstrated that serum lncRNA DLEU1 levels were significantly increased in patients with EC, and serum lncRNA DLEU1 showed good performance for discriminating EC patients from patients with endometrial hyperplasia and healthy controls. In addition, EC patients with advanced clinicopathological features had higher circulating lncRNA DLEU1 level than those with favorable clinical characteristics. Moreover, EC patients in the high serum lncRNA DLEU1 group suffered worse overall survival and disease-free survival than those in the low serum lncRNA DLEU1 group. Furthermore, multivariate cox regression analysis displayed that the serum lncRNA DLEU1 served as an independent prognostic factor for EC. Conclusions: Collectively, our study suggests that serum lncRNA DLEU1 is a novel and promising biomarker for prognostic estimation of EC.

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Development of an immune-related gene pairs signature for predicting clinical outcome in lung adenocarcinoma

Scientific Reports ◽

10.1038/s41598-021-83120-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chunlei Wu ◽

Quanteng Hu ◽

Dehua Ma

Keyword(s):

Overall Survival ◽

Regression Analysis ◽

Lung Adenocarcinoma ◽

Risk Score ◽

Cox Regression ◽

Related Gene ◽

Cox Regression Analysis ◽

Gene Pairs ◽

Immune Related Gene ◽

Pathological Subtype

AbstractLung adenocarcinoma (LUAD) is the main pathological subtype of Non-small cell lung cancer. We downloaded the gene expression profile and immune-related gene set from the TCGA and ImmPort database, respectively, to establish immune-related gene pairs (IRGPs). Then, IRGPs were subjected to univariate Cox regression analysis, LASSO regression analysis, and multivariable Cox regression analysis to screen and develop an IRGPs signature. The receiver operating characteristic curve (ROC) was applied for evaluating the predicting accuracy of this signature by calculating the area under ROC (AUC) and data from the GEO set was used to validate this signature. The relationship of 22 tumor-infiltrating immune cells (TIICs) to the immune risk score was also investigated. An IRGPs signature with 8 IRGPs was constructed. The AUC for 1- and 3-year overall survival in the TCGA set was 0.867 and 0.870, respectively. Similar results were observed in the AUCs of GEO set 1, 2 and 3 (GEO set 1 [1-year: 0.819; 3-year: 0.803]; GEO set 2 [1-year: 0.834; 3-year: 0.870]; GEO set 3 [1-year: 0.955; 3-year: 0.827]). Survival analysis demonstrated high-risk LUAD patients exhibited poorer prognosis. The multivariable Cox regression indicated that the risk score was an independent prognostic factor. The immune risk score was highly associated with several TIICs (Plasma cells, memory B cells, resting memory CD4 T cells, and activated NK cells). We developed a novel IRGPs signature for predicting 1- and 3- year overall survival in LUAD, which would be helpful for prognosis assessment of LUAD.

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NLRP3 is a Novel Prognostic Biomarker and Correlates With Immune Infiltrates in Lung Adenocarcinoma and Skin Cutaneous Melanoma

10.21203/rs.3.rs-880002/v1 ◽

2021 ◽

Author(s):

Chenxi Yuan ◽

Qingwei Wang ◽

Xueting Dai ◽

Yipeng Song ◽

Jinming Yu

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Lung Adenocarcinoma ◽

Immune Cells ◽

Cutaneous Melanoma ◽

Cox Regression ◽

Cox Regression Analysis ◽

Potential Biomarker ◽

The Impact ◽

Nlrp3 Expression

Abstract Background: Lung adenocarcinoma (LUAD) and skin cutaneous melanoma (SKCM) are common tumors around the world. However, the prognosis in advanced patients is poor. Because NLRP3 was not extensively studied in cancers, so that we aimed to identify the impact of NLRP3 on LUAD and SKCM through bioinformatics analyses. Methods: TCGA and TIMER database were utilized in this study. We compared the expression of NLRP3 in different cancers and evaluated its influence on survival of LUAD and SKCM patients. The correlations between clinical information and NLRP3 expression were analyzed using logistic regression. Clinicopathologic characteristics associated with overall survival in were analyzed by Cox regression. In addition, we explored the correlation between NLRP3 and immune infiltrates. GSEA and co-expressed gene with NLRP3 were also done in this study. Results: NLRP3 expressed disparately in tumor tissues and normal tissues. Cox regression analysis indicated that up-regulated NLRP3 was an independent prognostic factor for good prognosis in LUAD and SKCM. Logistic regression analysis showed increased NLRP3 expression was significantly correlated with favorable clinicopathologic parameters such as no lymph node invasion and no distant metastasis. Specifically, a positive correlation between increased NLRP3 expression and immune infiltrating level of various immune cells was observed. Conclusion: Together with all these findings, increased NLRP3 expression correlates with favorable prognosis and increased proportion of immune cells in LUAD and SKCM. These conclusions indicate that NLRP3 can serve as a potential biomarker for evaluating prognosis and immune infiltration level.

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