Potential Prognostic Biomarker For Non-small Cell Lung Cancer Research Articles

Identifying lncRNAs and mRNAs related to survival of NSCLC based on bioinformatic analysis and machine learning.

Non-small cell lung cancer (NSCLC) is the most common histopathological type, and it is purposeful for screening potential prognostic biomarkers for NSCLC. This study aims to identify the lncRNAs and mRNAs related to survival of non-small cell lung cancer (NSCLC). The expression profile data of lung adenocarcinoma and lung squamous cell carcinoma were downloaded in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset. A total of eight survival related long non-coding RNAs (lncRNAs) and 262 survival related mRNAs were filtered. By gene set enrichment analysis, 17 significantly correlated Gene Ontology signal pathways and 14 Kyoto Encyclopedia of Genes and Genomes signal pathways were screened. Based on the clinical survival and prognosis information of the samples, we screened eight lncRNAs and 193 mRNAs by single factor Cox regression analysis. Further single and multifactor Cox regression analysis were performed, 30 independent prognostication-related mRNAs were obtained. The PPI network was further constructed. We then performed the machine learning algorithms (Least absolute shrinkage and selection operator, Recursive feature elimination, and Random forest) to screen the optimized DEGs combination, and a total of 17 overlapping mRNAs were obtained. Based on the 17 characteristic mRNAs obtained, we firstly built a Nomogram prediction model, and the ROC values of training set and testing set were 0.835 and 0.767, respectively. By overlapping the 17 characteristic mRNAs and PPI network hub genes, three genes were obtained: CDC6, CEP55, TYMS, which were considered as key factors associated with survival of NSCLC. The in vitro experiments were performed to examine the effect of CDC6, CEP55, and TYMS on NSCLC cells. Finally, the lncRNAs-mRNAs networks were constructed.

LncRNA FAM138B inhibits the progression of non-small cell lung cancer through miR-105-5p

ABSTRACT As a type of lung cancer, non-small cell lung cancer (NSCLC) has the characteristics of high mortality and high recurrence rate, which poses a great threat to human life and health. Due to the high risk of surgical treatment and the slow recovery of wounds, non-coding RNAs, especially lncRNAs are used as new potential clinical prognostic markers to prevent and treat cancer in advance. This study aims to explore the role of FAM138B in NSCLC and its possibility as a prognostic biomarker. Real-timequantitative polymerase chain reaction (RT-qPCR) was used to detect the expression and overexpression level of lncRNA FAM138B (FAM138B) in cells and tissues. The CCK-8, Transwell migration and invasion methods were performed to observe the cell transfection.The interaction between FAM138B and miR-105-5p was predicted by the bioinformatics tool starBase v2.0, and verified by the luciferase reporter gene experiment. Kaplan-Meier and Cox regression analyses were used to determine the prognostic significance of FAM138B in NSCLC. The expression of FAM138B is down-regulated in NSCLC cells and tissues. Overexpression of FAM138B can inhibit the expression level of miR-105-5p in NSCLC cells, and the ability of NSCLC cells to proliferate, migrate and invade is downregulated. FAM138B targets miR-105-5p, and there is a negative correlation between FAM138B and miR-105-5p. It is confirmed that FAM138B inhibits the progression of NSCLC by targeting miR-105-5p and can be a potential prognostic biomarker for NSCLC.

High expression of RUVBL1 and HNRNPU is associated with poor overall survival in stage I and II non-small cell lung cancer patients

The present study aimed to investigate expression levels and prognostic significance of RUVBL1 and HNRNPU in stage I and II non–small-cell lung cancer (NSCLC) patients. Therefore, we evaluated immunohistochemical staining of RUVBL1 and HNRNPU, as well as RNA-seq data from public sources, and the results were evaluated concerning overall survival (OS) and clinicopathological features. We found that RUVBL1 and HNRNPU proteins and mRNA levels were higher in tumor tissues as compared to adjacent/normal tissues. RUVBL1 (p = 0.013) and HNRNPU (p = 0.021) high protein levels were independent prognostic factors for poor OS. Also, the multivariate analysis in the TCGA dataset revealed that high RUVBL1 (p = 0.064) and HNRNPU (p = 0.181) mRNA levels were not significantly associated with prognosis. However, the co-expression status of these markers (R + H +) was independently associated with poor OS both in the TCGA dataset (p = 0.027) and in our cohort (p = 0.001). In conclusion, combined and individual expression of RUVBL1 and HNRNPU proteins, as well as R + H + mRNA status, may serve as potential prognostic biomarkers for NSCLC. This study adds to the previous observations that RUVBL1 and HNRNPU might be novel and promising therapeutic targets and markers for prognostic evaluation.

Upregulation of Serum miR-629 Predicts Poor Prognosis for Non-Small-Cell Lung Cancer.

Non-small-cell lung cancer (NSCLC) is one of the most common types of cancer worldwide. Accumulating evidence has suggested that aberrant expression of microRNAs (miRNAs) is involved in the carcinogenesis and progression of NSCLC. The current study is aimed at investigating the clinical significance of serum miR-629 in NSCLC. The expression levels of serum miR-629 in patients with NSCLC, patients with nonmalignant lung diseases, and healthy controls were assessed by real-time quantitative polymerase chain reaction. Our results showed that serum miR-629 levels were significantly upregulated in NSCLC patients compared to the controls. Serum miR-629 exhibited better performance for discriminating NSCLC patients from healthy controls, compared to the traditional biomarkers CYFRA 21-1 and CEA. In addition, a high serum miR-629 level was positively correlated with adverse clinicopathological parameters including lymph node metastasis, differentiation, and clinical stage. Serum miR-629 was dramatically reduced in the NSCLC cases receiving surgical treatment. Moreover, the patients in the high serum miR-629 group suffered poorer overall survival and disease-free survival than those in the low serum miR-629 group. In conclusion, serum miR-629 might serve as a potential prognostic biomarker for NSCLC.

Integrated Analysis of lncRNA-miRNA-mRNA ceRNA Network Identified lncRNA EPB41L4A-AS1 as a Potential Biomarker in Non-small Cell Lung Cancer.

BackgroundRecent evidence has indicated that long non-coding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) to modulate mRNAs expression by sponging microRNAs (miRNAs). However, the specific mechanism and function of lncRNA-miRNA-mRNA regulatory network in non-small cell lung cancer (NSCLC) remains unclear.Materials and MethodsWe constructed a lung cancer related lncRNA-mRNA network (LCLMN) by integrating differentially expressed genes (DEGs) with miRNA-target interactions. We further performed topological feature analysis and random walk with restart (RWR) analysis of LCLMN. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to investigate the target DEGs in LCLMN. The expression levels of significant lncRNAs in NSCLC were validated by quantitative real-time PCR (RT-qPCR). The prognostic value of the potential lncRNA was evaluated by Kaplan-Meier analysis.ResultsA total of 33 lncRNA nodes, 580 mRNA nodes and 2105 edges were identified from LCLMN. Based on functional enrichment analysis and co-expression analysis, lncRNA EPB41L4A-AS1 was demonstrated to be correlated with the tumorigenesis of NSCLC. RT-qPCR results confirmed that the expression levels of lncRNA EPB41L4A-AS1 in NSCLC tissues were downregulated compared with adjacent non-cancerous tissues. Kaplan-Meier analysis showed that high expression of lncRNA EPB41L4A-AS1 was associated with better overall survival (OS) in NSCLC patients. Further investigation identified that high expression levels of COL4A3BP, CDS2, PURA, PDCD6IP, and TMEM245 were also correlated with better OS in NSCLC patients.ConclusionIn this study, we constructed a lncRNA-miRNA-mRNA ceRNA network to investigate potential prognostic biomarkers for NSCLC. We found that lncRNA EPB41L4A-AS1 could function as a regulator in the pathogenesis of NSCLC.

Abstract 5790: An epigenome-wide gene-age interaction analysis reveals opposite effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients

Abstract Introduction: Aging has become a global public health concern. The number of elderly lung cancer patients increased and elderly comprise the majority (81%) of non-small cell lung cancer (NSCLC) patients. DNA methylation is a potential prognostic biomarker for NSCLC, while it is also associated with aging. However, whether the association between DNA methylation and NSCLC survival is modified by aging is not known. Methods: After quality control procedures, we used a two-stage study design to identify DNA methylation-age interaction that associated with overall survival (OS) for early-stage adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients from four international collaborating study centers. In the discovery phase, we investigated the interaction effect in LUAD and LUSC using Cox proportional hazards model, adjusted for covariates. We confirmed the significant interactions with Bonferroni adjusted P ≤ 0.05 were further confirmed in the validation phase using The Cancer Genome Atlas (TCGA) database. Results: A total of 1,230 LUAD and LUSC patients were eligible for the study and 311,981 DNA methylation loci were evaluated. There were 613 (NLUAD = 492 and NLUSC = 121) patients in the discovery phase, and 617 (NLUAD = 332 and NLUSC = 285) patients in the validation phase, respectively. We identified one LUAD-specific CpG probe cg14326354PRODH, the effect on OS was significantly modified by age (HRinteraction = 0.989; 95% CI: 0.986-0.994; P = 9.18 × 10−7). The effect of DNA methylation on OS was different in young and elderly patients (young: HR = 2.44; 95% CI: 1.26-4.72; P = 8.34 × 10−3; elderly: HR = 0.58; 95% CI: 0.42-0.82; P = 1.67 × 10−3). Low methylation level benefited elderly LUAD patients. Moreover, there was an antagonistic interaction between low methylation of cg14326354PRODH and elder age (HRinteraction = 0.21; 95% CI: 0.11-0.40; P = 2.20 × 10−6). Conclusion: Low methylation of cg14326354PRODH may benefit the survival of elderly LUAD patients, providing new insight into only age-specific prediction, but also potential methylation-specific drug targeting. Citation Format: Li Su. An epigenome-wide gene-age interaction analysis reveals opposite effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5790.

Upregulation of microRNA-1303 is a potential prognostic marker of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, imposing a huge disease burden worldwide. MicroRNA-1303 (miR-1303) has been demonstrated to be involved in several diseases, including cancers. In this study, we aimed to investigate the role of miR-1303 in NSCLC. We quantified the expression levels of miR-1303 in NSCLC tissues and cells using the qRT-PCR assay. Then the association between miR-1303 expression and clinical characteristics of patients was analyzed using the χ2 test. The Kaplan-Meier and multivariate Cox regression assays were used to investigate the prognostic value of miR-1303 in NSCLC. Furthermore, the functional proliferation, migration, and invasion assays were used to explore the miR-1303 functions in vitro. The expression of miR-1303 was upregulated in NSCLC tissue samples and cells. The upregulation of miR-1303 was associated with TNM stage and lymph node metastasis. The survival time of NSCLC patients with high expression of miR-1303 was shorter than those with low expression. The functional analyses revealed that overexpression of miR-1303 in H1299 and A549 cells promoted cell proliferation, migration, and invasion. These results suggest that miR-1303 may be a potential prognostic biomarker for NSCLC and be involved in the progression of NSCLC.

Identification of key genes and construction of microRNA-mRNA regulatory networks in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most common type of lung tumor. Deregulation of microRNA may be involved in the occurrence of NSCLC and we aimed to find the potential prognostic biomarkers for NSCLC. The microRNA microarray expression profiles were downloaded from GEO dataset and then generated by applying robust multi-array average (RMA). The normalized data was analyzed with a Bioconductor package linear model for microarray data and an independent dataset was used to inspect the results. Then, the differentially expressed genes were identified using the limma package. Besides, in order to investigate the function of the differentially expressed microRNA in NSCLC, the GO and KEGG functional enrichment analysis were applied, and the GSEA analysis was performed for mining the therapeutic candidates. A total of 160 differentially expressed microRNAs were identified, among which 37 microRNAs showed significant expression changes (up-regulated and down-regulated) with the same method in the validation dataset GSE74190. Multiple cancer-related pathways, such as AMPK signaling pathway, AMPK signaling pathway, non-small cell lung cancer signaling pathway, were determined by performing the functional enrichment analysis. Besides, the results of GSEA analysis showed that the CCND1 was mostly enriched in lung cancer group. In conclusion, a set of differentially expressed microRNAs in NSCLC was identified and the CCND1 gene was determined as the potential prognostic biomarkers for NSCLC, providing useful information for discovery of future therapeutic targets and candidates in the clinical management of NSCLC.

B3GNT3 overexpression is associated with unfavourable survival in non-small cell lung cancer

ObjectiveThe aim of this study was to evaluate the expression of beta-1,3-N-acetylglucosaminyltransferase-3 (B3GNT3) in non-small cell lung cancer (NSCLC) patients and to investigate the relevance of B3GNT3 expression in tumour...

APRIL promotes non-small cell lung cancer growth and metastasis by targeting ERK1/2 signaling.

Non-small-cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the most common cause of cancer-related mortality in the world. It is a complex disease involving multiple genetic alterations. As a cytokine belonging to the Tumor Necrosis Factor-α (TNF- α) family, the - a proliferation-inducing ligand (APRIL) expression and its signaling have been studied in many human solid tumor types, but the data on APRIL signaling in NSCLC are lacking. The aim of this study was to evaluate the APRIL expression and investigate its signaling in NSCLC. The expression of APRIL and its receptors, B cell maturation antigen (BCMA) and transmembrane activator and calcium-modulatorand cyclophilin ligand interactor (TACI), was analyzed by using immunohistochemistry in NSCLC samples. Quantitative RT-PCR was performed to evaluate mRNA expression of APRIL, BCMA and TACI in human lung adenocarcinoma cell lines A549, H1299, and H1650. Cell proliferation was measured by using the cell proliferation and cytotoxicity assay kit 8 (CCK8) assay, cell migration by using wound healing assay, and cell invasion by using transwall assay. The protein level of APRIL, BCMA and TAC, and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) signaling, were determined by western blot. Our results indicated, APRIL and its receptors BCMA and TACI, were overexpressed in most of human NSCLC samples and cell lines; APRIL promoted tumor proliferation, migration and metastasis in A549 and H1299 cells via BCMA and TACI. Furthermore, ERK1/2 activation was involved in APRIL signaling through TACI but not BCMA in A549 and H1299 cells. APRIL might serve as a potential prognostic biomarker for NSCLC, and APRIL related signaling pathway could be a therapeutic target for NSCLC.

TRIM59 is a novel potential prognostic biomarker in patients with non-small cell lung cancer: A research based on bioinformatics analysis.

Lung cancer is the leading cause of cancer-associated mortality worldwide and its prognosis is poor. Few effective biomarkers for non-small cell lung cancer (NSCLC) have been translated into the clinical practice aiming to assist in the treatment plan design and prognosis evaluation. The aim of the present study was to identify novel potential prognostic biomarkers for NSCLC. Tripartite motif 59 (TRIM59) was identified from a microarray dataset of matched-samples and was verified as an aberrantly upregulated gene in NSCLC tissue. The expression level of TRIM59 in NSCLC subtypes was observed to be significantly increased in large cell lung carcinoma and squamous cell carcinoma as compared with that in adenocarcinoma. Its expression correlated with several clinicopathological features, including gender, smoking habits, and unfavorable tumor node and pathological stages. Notably, TRIM59 demonstrated a negative correlation with survival time and its overexpression indicated a poor prognosis in NSCLC. Furthermore, univariate and multivariate Cox's regression analyses indicated that TRIM59 was an independent prognostic factor in tumor tissue as compared with age, gender, tumor stage, node stage, and metastasis. Gene set enrichment analysis and protein-protein interaction network construction revealed that TRIM59 was associated with oncogenic mammalian target of rapamycin (MTOR) and eukaryotic initiation factor 4E (EIF4E) signaling through ubiquitin C binding. In conclusion, it was revealed that TRIM59 is a novel prognostic biomarker modulating oncogenic MTOR and EIF4E signaling pathways in NSCLC. These findings provided a novel insight into the clinical application of TRIM59. Therefore, TRIM59 may serve as an independent predictor for prognosis and a potential therapeutic target for NSCLC.

KIAA1522 is a novel prognostic biomarker in patients with non-small cell lung cancer.

Nowadays, no robust biomarkers have been applied to clinical practice to provide prognostic evaluation of non-small cell lung cancer (NSCLC). This study aims to identify new potential prognostic biomarkers for NSCLC. In the present work, KIAA1522 is screened out from two independent GEO datasets as aberrantly up-regulated gene in NSCLC tissues. We evaluate KIAA1522 expression immunohistochemically in 583 NSCLC tissue samples and paired non-tumor tissues. KIAA1522 displays stronger staining in NSCLC cases than in adjacent normal lung tissues. Importantly, patients with KIAA1522 overexpression had a significantly shorter overall survival compared to those with low expression (P < 0.00001). Multivariate Cox regression analyses show that KIAA1522 is an independent prognostic indicator, even for early-stage NSCLCs (P = 0.00025, HR = 2.317, 95%CI: 1.477–3.635). We also found that high expression of KIAA1522 is a significant risk factor for decreased overall survival of the patients who received platinum-based chemotherapy. Gene set enrichment analysis (GSEA) and functional studies reveal that KIAA1522 is associated with oncogenic KRAS pathways. Taken together, high expression of KIAA1522 can be used as an independent biomarker for predication of poor survival and platinum-resistance of NSCLC patients, and aberrant KIAA1522 might be a new target for the therapy of the disease.

MiR-1290 is a potential prognostic biomarker in non-small cell lung cancer.

miR-1290 is a newly discovered microRNA (miRNA), and its role in non-small cell lung cancer (NSCLC) remains unknown. This study aimed to evaluate the expression levels of miR-1290 in NSCLC tissues and serum, and explore its associations with clinicopathological characteristics and prognosis of NSCLC patients. A total of 33 pairs of tissues and 73 serum samples were obtained from NSCLC patients and expression levels of miR-1290 were detected by specific TaqMan qRT-PCR. The relationship between miR-1290 expression levels in NSCLC tissues and serum and clinicopathological characteristics was estimated respectively. The correlation between serum miR-1290 expression levels and overall survival of NSCLC patients was performed by Kaplan-Meier analysis and Cox proportional hazards model. We determined that miR-1290 expression levels were increased significantly in NSCLC tissues compared with non-tumor adjacent normal tissues, and higher miR-1290 expression levels were positively correlated with high tumor stage (P=0.004) and positive lymph node metastasis (P=0.013). Compared with benign lung disease and healthy controls, serum levels of NSCLC patients exhibited higher expression of miR-1290. Furthermore, the up-regulation of serum miR-1290 more frequently occurred in NSCLC patients with high TNM stage, positive lymph node metastasis (P=0.022 and P=0.024, respectively). Kaplan-Meier analysis demonstrated that high serum miR-1290 expression levels predicted poor survival (P=0.022). Cox proportional hazards risk analysis indicated that miR-1290 was an independent prognostic factor for NSCLC. Our study suggests that miR-1290 is overexpressed in NSCLC, and serum miR-1290 may be used as a potential prognostic biomarker for NSCLC.

Expression of microRNA miR-126 and miR-200c is associated with prognosis in patients with non-small cell lung cancer.

MicroRNAs (miRNAs) are short non-coding RNAs that exert a critical influence on tumorigenesis through post-transcriptional modification and are considered to be potential biomarkers for the diagnosis or prognosis of various cancers. Although several miRNAs have been proposed as relevant biomarkers for non-small cell lung cancer (NSCLC), detailed working mechanisms and validated prognostic significance of these miRNAs remain controversial. In this study, we evaluated expression levels of miRNA-126 (miR-126) and miR-200c in 72 NSCLCs and 30 benign lung tissues by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and analyzed the correlation of miRNA expression with a variety of clinicopathological factors and patient survival. Compared with the benign control group, miR-126 expression was significantly downregulated in NSCLCs (p < 0.001), while miR-200c expression was significantly upregulated in NSCLCs (p < 0.001). The expression of miR-126 was significantly higher in NSCLCs with a tumor size of ≤3 cm than in those with a tumor size of >3 cm (p = 0.026). There were no other significant associations between miRNA expression and clinicopathological features. In univariate survival analysis for all NSCLC patients, high miR-200c expression (p = 0.037), large tumor size (p = 0.026), and lymphovascular invasion (p = 0.012) were significantly correlated with worse overall survival. High miR-126 expression was significantly associated with favorable prognosis only in patients with adenocarcinoma (p = 0.033). In multivariate analysis, miR-200c and tumor size remained as independent prognostic factors. Our results suggest that miR-126 might play tumor-suppressive and miR-200c an oncogenic role, and these miR's are potential prognostic biomarkers for NSCLC.