scholarly journals A Signature of 14 Long Non-Coding RNAs (lncRNAs) as a Step towards Precision Diagnosis for NSCLC

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 439
Anetta Sulewska ◽  
Jacek Niklinski ◽  
Radoslaw Charkiewicz ◽  
Piotr Karabowicz ◽  
Przemyslaw Biecek ◽  

LncRNAs have arisen as new players in the world of non-coding RNA. Disrupted expression of these molecules can be tightly linked to the onset, promotion and progression of cancer. The present study estimated the usefulness of 14 lncRNAs (HAGLR, ADAMTS9-AS2, LINC00261, MCM3AP-AS1, TP53TG1, C14orf132, LINC00968, LINC00312, TP73-AS1, LOC344887, LINC00673, SOX2-OT, AFAP1-AS1, LOC730101) for early detection of non-small-cell lung cancer (NSCLC). The total RNA was isolated from paired fresh-frozen cancerous and noncancerous lung tissue from 92 NSCLC patients diagnosed with either adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC). The expression level of lncRNAs was evaluated by a quantitative real-time PCR (qPCR). Based on Ct and delta Ct values, logistic regression and gradient boosting decision tree classifiers were built. The latter is a novel, advanced machine learning algorithm with great potential in medical science. The established predictive models showed that a set of 14 lncRNAs accurately discriminates cancerous from noncancerous lung tissues (AUC value of 0.98 ± 0.01) and NSCLC subtypes (AUC value of 0.84 ± 0.09), although the expression of a few molecules was statistically insignificant (SOX2-OT, AFAP1-AS1 and LOC730101 for tumor vs. normal tissue; and TP53TG1, C14orf132, LINC00968 and LOC730101 for LUAD vs. LUSC). However for subtypes discrimination, the simplified logistic regression model based on the four variables (delta Ct AFAP1-AS1, Ct SOX2-OT, Ct LINC00261, and delta Ct LINC00673) had even stronger diagnostic potential than the original one (AUC value of 0.88 ± 0.07). Our results demonstrate that the 14 lncRNA signature can be an auxiliary tool to endorse and complement the histological diagnosis of non-small-cell lung cancer.

2021 ◽  
Zixiao Liu ◽  
Xudong Liu ◽  
Yu Zhang ◽  
Yongjie Zhou ◽  
Shuaibin Lian ◽  

Abstract Lung cancer is very difficult to diagnose in the its early stages because of its initial asymptomatic characteristics. In recent years, pyrolysis has been shown identified as a novel type of programmed cell death with inflammation mediated by the gasdermin family. In this study, 33 differentially-expressed pyroptosis-related genes were commonly identified in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. Tumor-related gasdermin family genes that were significantly differentially expressed in non-small cell lung cancer (NSCLC) tissues were identified by our co-expression network analysis. Among them, the mRNA level of GSDMB gene had significant impacts on tumor staging and survival rates of NSCLC patients. Therefore, this gene is a potential new therapeutic target for the treatment of NSCLC. In addition, the high expression levels of GSDMC/D were significantly correlated with the low overall survival (OS), progression-free survival (FP) and post-progression survival (PPS) of NSCLC patients. Therefore, this gene is a potential oncogene for NSCLC. Furthermore, four small molecules (erastin, cefotiam, metanephrine, and vorinostat) that could most significantly reverse the NSCLC gene expression were identified. They interacted with GSDMB proteins mainly through H-bonds and hydrophobic interactions. This study provides new therapeutic targets and prognostic makers for NSCLC patients.

2021 ◽  
Vol 27 ◽  
Jin Ma ◽  
Rao Du ◽  
Yan Huang ◽  
Wen Zhong ◽  
Huan Gui ◽  

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. The nuclear factor of activated T cells (NFAT) family is implicated in tumorigenesis and progression in various types of cancer. However, little is known about their expression patterns, distinct prognostic values, and potential regulatory networks in NSCLC. In this study, we comprehensively analyzed the distinct expression and prognostic value of NFATs in NSCLC through various large databases, including the Oncomine, UCSC Xena Browser, UALCAN databases, Kaplan–Meier Plotter, cBioPortal, and Enrichr. In lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), NFAT1/2/4/5 mRNA expression levels were significantly decreased and NFAT3 mRNA expression level was significantly increased. The cBioPortal database analysis showed that the mRNA dysregulation was one of the single most important factors for NFAT alteration in LUAD and LUSC and that both LUAD and LUSC cases with the alterations in the mRNA expression of NFATs had significantly better overall survival (OS). High expression levels of NFAT1/2/4/5 were significantly associated with better OS in LUAD, whereas high NFAT3 expression led to a worse OS. Overexpression of NFAT1/2 predicted better OS in LUSC, whereas high NFAT5 expression led to a worse OS. The networks for NFATs and the 50 most frequently altered neighbor genes in LUAD and LUSC were also constructed. NFATs and genes significantly associated with NFAT mRNA expression in LUAD and LUSC were significantly enriched in the cGMP-dependent protein kinase and Wnt signaling pathways. These results showed that the NFAT family members displayed varying degrees of abnormal expressions, suggesting that NFATs may be therapeutic targets for patients with NSCLC. Aberrant expression of NFATs was found to be associated with OS in the patients with NSCLC; among NFATs, NFAT3/4 may be new biomarkers for the prognosis of LUAD. However, further studies are required to validate our findings.

2020 ◽  
Vol 19 ◽  
pp. 153303382097066
Xiaoguang Qi ◽  
Chunyan Qi ◽  
Tao Wu ◽  
Yi Hu

Objective: Precision immunotherapy in non-small cell lung cancer (NSCLC) have been the focus of tumor immunity research. The aim of this study is to identify novel candidate biomarkers predicting the response to immunotherapy in NSCLC. Methods: GSE126044 was obtained from Gene Expression Omnibus (GEO). According to the response to anti-PD-1 antibody, 2 groups were divided: response group and non-response group. Differentially expressed genes (DEGs) were screened using R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. ROC curves and possible pathways of the seed genes were further analyzed. Results: In total, 588 DEGs (487 upregulated DEGs and 101 downregulated) were identified. GO and KEGG analyses showed that upregulated DEGs were mainly enriched in immune response and cell adhesion pathways, while VEGF signaling pathway and metabolic pathways were mainly enriched in downregulated DEGs. In addition, CSF1 R and HCST showed more powerful predictive ability than PDL1. More importantly, these candidate genes were not only positively correlated with the expression of PDL1 and the infiltration of CD8+ T cells in the immune microenvironment, but also might improve the prognosis in lung squamous cell carcinoma. Conclusions: CSF1 R and HCST might be novel predictive markers for immunotherapy in NSCLC.

2020 ◽  
Vol 19 (17) ◽  
pp. 2060-2071
Lei Zhang ◽  
Yifang Huang ◽  
Xuedong Gan ◽  
Siying He ◽  
Xiaohuan Cheng ◽  

Background: Atorvastatin belongs to the group of statins and is the leading drug for hypercholesterolemia treatment. Although, its anticancer effects are highly appreciated, its properties are still unclear. The aim of this study was to explore the underlying anticancer mechanisms induced by atorvastatin and enlarge the potential target in non-small cell lung cancer. Methods: arget genes of atorvastatin were collected by the DrugBank database. Prediction of interaction between primary targets and secondary targets was performed, and protein-protein interaction network was constructed though the STRING. Then, KEGG pathway enrichment analysis was performed with WebGestalt and ClueGO, including the pathways in non-small cell lung cancer. Furthermore, a genomic alteration analysis of the selected seed genes of atorvastatin benefit and non-small cell lung cancer pathway was conducted by cBioPortal. Finally, a survival analysis with the selected seed genes in lung cancer (lung adenocarcinoma, lung squamous cell carcinoma) was conducted using Kaplan-Meier (KM) plotter. Results: To identify seed genes, 65 potential candidate genes were screened as targets for atorvastatin using STRING with DrugBank database, while the KEGG pathway was enriched to get the overlap match of pathways in non-small cell lung cancer. Then 4 seed genes, Epidermal Growth Factor Receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ERBB2), AKT serine/threonine kinase 1 (AKT1) and tumor protein p53 (TP53), were selected and their genomic alternation were evaluated by cBioPortal. Survival analysis found that TP53 and EGFR showed a significant correlation (log rank P = 3e-07 and 0.023) with lung adenocarcinoma and lung squamous cell carcinoma, according to the KM analysis. Conclusion: Gene-phenotype connectivity for atorvastatin in non-small cell lung cancer was identified using functional/activity network analysis method, and our findings demonstrated that TP53 and EGFR could be the potential targets in cancer patients with atorvastatin therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21023-e21023
Yuan Qiu ◽  
Haihong Yang ◽  
Hanzhang Chen ◽  
Qiuhua Deng ◽  
Liping Liu ◽  

e21023 Background: TMB is associated with mono-immunotherapy efficacy for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). For early-stage NSCLC or EGFR mutated non-resectable NSCLC, TMB-H predicted better prognosis or poor response to TKIs. This research might develop potential predictive parameters for distinguishing NSCLC with high or low TMB. Methods: Samples of surgically resected, cancer tissues were collected from 499 patients with NSCLC: 29 (5.8%) lung squamous cell carcinoma (LUSC) and 468 (94.2%) lung adenocarcinoma (LUAD). The mutations and TMB were confirmed by target region capture sequencing (Oseq™-508). Results: According to the median value (3.08), TMB is divided into high (N = 244) and low (N = 255). Interactions between TMB and sex, age, location, histology, pathological subtype, lymph node, parabronchial lymph node, LVI, neuro-invasive, stage and mutation status were evaluated. The distribution of TMB-H was significantly (p < 0.001) correlated with sex, age, histology, pathological subtype, stage (TN stage) and partial mutations. Among all mutations, 6 genes (TP53 / FAT3 / KMT2D / TSHZ3 / NAV3 / EPHA3) were confirmed to be significantly related to TMB-H in NSCLC. We also found that TMB-H was significantly affected by mutation status of KRAS gene (P. G12X, p < 0.001) and missense mutations in FAT3 (p < 0.001). The Kruskal–Wallis H test results showed that the mutation types of FAT3, KRAS, TP53 and PIK3CA were closely related to TMB-H. Lasso linear regression analysis was applied and resulted the better predictors of TMB status including TSHZ3, KMT2D, TP53, gender and T stage. Conclusions: Instead of comprehensive genomic profiling to evaluate TMB, clinical characteristics and special mutation types may help to effectively screen and predicate patients with TMB-H status. [Table: see text]

2021 ◽  
Vol 11 ◽  
Yuepeng Zhang ◽  
Kai Mi ◽  
Zhiheng Li ◽  
Lixia Qiang ◽  
Meiyu Lv ◽  

BackgroundA detailed means of prognostic stratification in patients with non-small cell lung cancer (NSCLC) is urgently needed to support individualized treatment plans. Recently, microRNAs (miRNAs) have been used as biomarkers due to their previously reported prognostic roles in cancer. This study aimed to construct an immune-related miRNA signature that effectively predicts NSCLC patient prognosis.MethodsThe miRNAs and mRNA expression and mutation data of NSCLC was obtained from The Cancer Genome Atlas (TCGA). Immune-associated miRNAs were identified using immune scores calculated by the ESTIMATE algorithm. LASSO-penalized multivariate survival models were using for development of a tumor immune-related miRNA signature (TIM-Sig), which was evaluated in several public cohorts from the Gene Expression Omnibus (GEO) and the CellMiner database. The miRTarBase was used for constructing the miRNA-target interactions.ResultsThe TIM-Sig, including 10 immune-related miRNAs, was constructed and successfully predicted overall survival (OS) in the validation cohorts. TIM-Sig score negatively correlated with CD8+ T cell infiltration, IFN-γ expression, CYT activity, and tumor mutation burden. The correlation between TIM-Sig score and genomic mutation and cancer chemotherapeutics was also evaluated. A miRNA-target network of 10 miRNAs in TIM-Sig was constructed. Further analysis revealed that these target genes showed prognostic value in both lung squamous cell carcinoma and adenocarcinoma.ConclusionsWe concluded that the immune-related miRNAs demonstrated a potential value in clinical prognosis.

2019 ◽  
Zhongxiang Tang ◽  
Lili Wang ◽  
Pei Dai ◽  
Pinglang Ruan ◽  
Dan Liu ◽  

AbstractBackgroudThe study was designed to explore the role of GIMAP family in non-small cell lung cancer (NSCLC) and its possible expression regulation mechanisms using existing biological databases including encyclopedia of DNA elements (ENCODE), gene expression omnibus (GEO), and the cancer genome atlas (TCGA).MethodsLung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were used to evaluate the expression of GIMAPs in TCGA. Five NSCLC datasets were then selected from GEO for validation. RNA-seq and Chip-seq data from ENCODE and GEO were used to observe epigenetic modifications on the chromosomes of GIAMPs in NSCLC. We constructed protein-protein interaction (PPI) network to reveal the main interacting proteins of GIMAPs. We then analyzed the correlation and regulatory mechanism between TAL1 and the expression of GIMAP family. We also used Kaplan-Meier for survival analysis.ResultsAll 7 genes in the GIMAP family were down-regulated in NSCLC. H3K4me3 and H3K27ac disappeared, while H3K27me3 increased on the chromosome of this family. The expression of TAL1 was positively correlated with the expression of GIMAPs. sh-TAL1 significantly down-regulated the expression of GIMAP family through epigenetic modification. High expression of GIMAPs and TAL1 was found to be associated with a good prognosis of NLCSC.ConclusionThe downregulation of TAL1 caused the disappearance of H3K27ac and H3K4me3. It also caused an increase in H3K27me3 on the GIMAPs gene, eventually leading to the overall downregulation of the GIMAP family genes.

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