Survival In Lung Adenocarcinoma Research Articles

BTN3A2 Expression Is Connected With Favorable Prognosis and High Infiltrating Immune in Lung Adenocarcinoma.

Background: Butyrophilin subfamily 3 member A2 (BTN3A2) is an important mediator in immune activation, and it is reported to be linked to many cancer progresses. However, the relation with infiltrating immune and prognosis of BTN3A2 in lung adenocarcinoma are not clear. Methods: In our study, we checked the mRNA expression and protein expression profile of BTN3A2 in lung adenocarcinoma (LUAD) and its relation to clinical outcomes using TIMER and UALCAN databases. In addition, we analyzed the survival of BTN3A2 in LUAD using the Kaplan–Meier Plotter database and PrognoScan database. Moreover, we analyzed gene set enrichment analysis (GSEA) of the BTN3A2. Next, we explored the relation of BTN3A2 expression with the immune infiltration by TIMER. At last, in order to enrich the regulatory mechanism of BTN3A2, we used miRarbase, starbase, and miRDB databases to look for miRNA targets of BTN3A2. Results: The mRNA along with the protein expression of BTN3A2 in the LUAD group was lower than that in the normal group. In addition, high BTN3A2 expression was connected with good first progression (FP) and overall survival (OS) in LUAD. Then, the GSEA analysis demonstrated that T-cell receptor signaling cascade, B-cell receptor signaling cascade, natural killer cell–mediated cytotoxicity, immune receptor activity, immunological synapse, and T-cell activation were enriched differentially in the BTN3A2 high expression phenotype of LUAD. Moreover, BTN3A2 expression is a remarkable positive correlation with invading levels of tumor purity, B cells, neutrophils, CD4+ T cells, dendritic cells, macrophages, and CD8+ T cells in LUAD, and B cells and dendritic cells were linked with a good prognosis of LUAD. To further enrich the possible regulatory mechanisms of BTN3A2, we analyzed the miRNA targets. The results showed that hsa-miR-17-5p may be miRNA targets of BTN3A2. Conclusion: Taking together, we provide evidence of BTN3A2 as possible prognosis biomarkers of LUAD. In addition, high BTN3A2 expression in LUAD may influence the prognosis because of immune invasion. Moreover, our findings provide a potential mechanism that hsa-miR-17-5p may be miRNA targets of BTN3A2.

Development and validation of endoplasmic reticulum stress-related eight-gene signature for predicting the overall survival of lung adenocarcinoma

BackgroundThe high case-fatality rate of patients with lung adenocarcinoma (LUAD) emphasizes the importance of identifying a robust and reliable prognostic signature for LUAD patients. Endoplasmic reticulum (ER) stress results from protein misfolding imbalance and has been shown to participate in the development of cancer. We aimed to develop and validation a reliable and robust ER stress-related prognostic signature to accurately predict prognosis for patients with LUAD.MethodsThe mRNA expressions data and the clinical information were downloaded from The Cancer Genome Atlas (TCGA) as training set. The data of external validation sets were downloaded from GEO database with the accession number GSE 30219, GSE 31210, GSE 50081 and GSE 37745. Univariate Cox regression analyses was performed to identify mRNAs associated with overall survival (OS) in LUAD. ER-associated genes were retrieved using GeneCards database. Next, we construct the best risk score model by the least absolute shrinkage and selection operator (LASSO) regression with tenfold cross-validation. Subsequently, predictive models and risk scores were developed in the TCGA training dataset. Cox proportional hazards regression models were used for univariate and multivariate analysis of risk score and clinicopathologic characteristics. As a validation set GSE30219, GSE31210 and (GSE50081+GSE37745) were used to validate the predictive performance of the model in TCGA. Finally, functional enrichment analysis, including the gene ontology (GO) enrichment analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and gene set enrichment analysis (GSEA) were performed to further explore function and mechanisms.ResultsA prognostic prediction model based on eight genes was developed in the TCGA training dataset. As expected, in validation sets, patients with higher risk scores were found to have worse prognosis. Time-dependent ROC curve analyses demonstrated that the risk score model was reliable. The nomograms showed excellent predictive ability. Multivariate Cox regression analyses indicated that the risk score was an independent prognostic factor for LUAD. Additionally, functional enrichment analysis showed that the relevant biomarkers were enriched in cell cycle and glycolysis related signaling pathways.ConclusionsThe 8-gene signature may enable improved the prediction of clinical events and decisions about management of LUAD.

Identification of a three-gene expression signature and construction of a prognostic nomogram predicting overall survival in lung adenocarcinoma based on TCGA and GEO databases.

BackgroundLung adenocarcinoma (LUAD) is the major cause of cancer mortality. Traditional prognostic factors have limited importance after including other parameters. Thus, developing a more credible prognostic model combined with genes and clinical parameters is necessary.MethodsThe messenger RNA (mRNA) expression and clinical information from The Cancer Genome Atlas (TCGA)-LUAD datasets and microarray data from three Gene Expression Omnibus (GEO) databases were obtained. We identified differentially-expressed genes (DEGs) between lung tumor and normal tissues through integrated analysis of the three GEO datasets. Univariate and multivariate Cox regression analyses were conducted to select survival-associated DEGs and to establish a prognostic gene signature which was associated with overall survival (OS). The expression of gene proteins was assessed in 180 LUAD tissue microarrays (TMAs) by immunohistochemistry (IHC). We verified its predictive performance with a Kaplan-Meier (KM) curve, receiver operating characteristic (ROC) curve, and Harrell’s concordance index (C-index) and validated it in external GEO databases. Multivariate Cox regression analysis was performed to identify the significant prognostic indicators in LUAD. Furthermore, we established a prognostic nomogram based on TCGA-LUAD dataset.ResultsA three-gene signature was constructed to predict the OS of LUAD patients. The KM analysis, ROC curve, and C-index present a good predictive ability of the gene signature in TCGA dataset [P<0.0001; C-index 0.6375; 95% confidence interval (CI): 0.5632–0.7118; area under the ROC curve (AUC) 0.674] and the external GEO datasets (P=0.05, 0.004, and 0.04, respectively). Univariate and multivariate Cox regression analyses also verified that LUAD patients with low-risk scores had a decreased risk of death compared to those with a high-risk score in TCGA database [hazard ratio (HR) =0.3898; 95% CI: 0.1938–0.7842; P<0.05]. Finally, we constructed a nomogram integrating the gene signature and clinicopathological parameters (P<0.0001; C-index 0.762; 95% CI: 0.714–0.845; AUC 0.8136). Compared with conventional staging, a nomogram can effectively improve prognosis prediction.ConclusionsThe nomogram is closely associated to the OS of LUAD patients. This consequence may be beneficial to individualized treatment and clinical decision-making.

Expressional regulation of NKG2DLs is associated with the tumor development and shortened overall survival in lung adenocarcinoma

Natural killer group 2D ligands (NKG2DLs) are expressed on tumor cells as a ligand for Natural killer group 2D (NKG2D) receptors. NKG2DLs interact with NKG2D to induce immune cell-mediated cytotoxicity for eliminating tumors. Studies demonstrated that tumor cells can reduce NKG2DLs’ expression to escape from anti-tumor immunity, leading to an aggressive cancer phenotype and poor prognosis in some cancers. However, these studies are limited and there is no comprehensive work on the regulation of NKG2DLs in lung adenocarcinoma (LUAD) which is one of the deadliest cancers worldwide. Here, we conducted an in silico analysis to evaluate the changes in NKG2DLs in LUAD by analyzing The Cancer Genome Atlas and the Gene Expression Omnibus datasets including tumor vs. normal comparisons, TNM stages, survival and infiltrating immune estimation profile. Results indicated that some members of NKG2DL were downregulated in LUAD as compared to normal samples. We determined that MICA (MHC class I polypeptide-related sequence A) was the most and significantly downregulated ligand among others and the results were nearly consistent with the different datasets which we used. Furthermore, survival analysis revealed that down-regulated MICA transcript expression might be one of the prognostic indicators of LUAD. Interestingly, according to the immune cell infiltrating analysis, there wasn’t a direct correlation between the MICA transcript expression and immune cell infiltration, while for MICB there was. In addition, in genetic alteration, DNA methylation and miRNA analyses, we did not observe critical outcomes that would clarify the down-regulated MICA expression in detail. Regardless, this study is highly comprehensive and contributes valuable suggestions to further functional studies about the regulation of NKG2DLs and promising immunotherapeutic approaches in LUAD.

A TP53 Related Immune Prognostic Model for the Prediction of Clinical Outcomes and Therapeutic Responses in Lung Adenocarcinoma.

TP53 is the most frequently mutated gene in lung adenocarcinoma (LUAD). The tumor immune microenvironment (TIM) is considered a vital factor that influences tumor progression and survival rate. The influence of TP53 mutation on TIM in LUAD has not been fully studied. Here we systematically investigated the relationship and potential mechanisms between TP53 mutation status and immune response in LUAD. We constructed an immune prognostic model (IPM) using immune associated genes, which were expressed differentially between the TP53 mutant and wild type LUAD patients. We discovered that TP53 mutations were significantly associated with 5 immune related biological processes. Thirty-six immune genes were expressed differentially between TP53 mutant and wild type LUAD patients. An IPM was constructed using 3 immune genes to differentiate the prognostic survival in LUAD. The high-risk LUAD group displayed significantly higher proportions of dendritic cell resting, T cell CD4 memory resting and mast cell resting, and significantly low proportions of dendritic cell activated, T cell CD4 memory activated, and mast cell activated. Moreover, IPM was found to be an independent clinical feature and can be used to predict immunotherapy responses. In summary, we constructed and validated an IPM using 3 immune related genes, which provides a better understanding of the mechanism from an immunological perspectives.

Characterization of the Oncogenic Potential of Eukaryotic Initiation Factor 4A1 in Lung Adenocarcinoma via Cell Cycle Regulation and Immune Microenvironment Reprogramming.

Simple SummaryLung cancer is a common cancer throughout the world. Despite advanced treatment strategies, the outcome is still poor. Based on the results of the present study, EIF4A1 interacting with EIF4H manipulates cell cycle regulation and immune microenvironment reprogramming in lung adenocarcinoma. The results specify EIF4A1 in lung adenocarcinoma tumorigenesis. Treatment derived from EIF4A1 would be worthy of further investigation.Lung adenocarcinoma (LUAD) is a common type of lung cancer. Although the diagnosis and treatment of LUAD have significantly improved in recent decades, the survival for advanced LUAD is still poor. It is necessary to identify more targets for developing potential agents against LUAD. This study explored the dysregulation of translation initiation factors, specifically eukaryotic initiation factors 4A1 (EIF4A1) and EIF4A2, in developing LUAD, as well as their underlying mechanisms. We found that the expression of EIF4A1, but not EIF4A2, was higher in tumor tissue and associated with poor clinical outcomes in LUAD patients. Elevated expression of EIF4H with poor prognosis may potentiate the oncogenic role of EIF4A1. Functional enrichment analysis revealed that upregulation of EIF4A1 was related to cell cycle regulation and DNA repair. The oncogenic effect of EIF4A1 was further elucidated by Gene Set Variation Analysis (GSVA). The GSVA score of the gene set positively correlated with EIF4A1 was higher in tumors and significantly associated with worse survival. In the meantime, gene set enrichment analysis (GSEA) also indicated that elevated EIF4A1 expression in LUAD patients was associated with a decreased infiltration score for immune cells by reducing anticancer immune cell types and recruiting immunosuppressive cells. Consistent with the results, the GSVA score of genes whose expression was negatively correlated with EIF4A1 was lower in the tumor tissue of LUAD cases with worse clinical outcomes and was strongly associated with the disequilibrium of anti-cancer immunity by recruiting anticancer immune cells. Based on the results from the present study, we hypothesize that the dysregulation of EIF4A1 might be involved in the pathophysiology of LUAD development by promoting cancer growth and changing the tumor immune microenvironment. This can be used to develop potential diagnostic biomarkers or therapeutic targets for LUAD.

The Expression of RTN1 in Lung Adenocarcinoma and Its Effect on Immune Microenvironment

背景与目的网状体家族基因1(Reticulon family gene 1, RTN1)是一种与内质网相关的网状体编码基因。RTN1在神经内分泌细胞的膜运输或神经内分泌分泌中起关键作用，同时RTN1可作为有神经内分泌成分的恶性肿瘤的潜在诊断/治疗标志物。然而在肺腺癌(lung adenocarcinoma, LUAD)患者中RTN1的表达情况及其对免疫微环境影响均未有报道。本研究旨在使用公共数据库和生物信息学网络工具研究RTN1在肺腺癌中的表达及其与肺腺癌中免疫浸润和存活的相关性。方法使用Tumor Immune Estimation Resource 2.0(TIMER 2.0)和Gene Expression Profiling Interactive Analysis 2(GEPIA 2)分析肿瘤和正常组织中RTN1 mRNA的表达水平。使用人类蛋白质图谱检查RTN1蛋白质表达。利用GEPIA2在线工具分析癌症基因组图谱(The Cancer Genome Atlas, TCGA)中RTN1的临床预后意义。为了进一步确认RTN1的潜在功能，使用基因集富集分析对数据进行了分析。此外，我们对来自肿瘤免疫单细胞中心(Tumor Immune Single-cell Hub, TISCH)数据库的两个数据集在单细胞测序水平上进行降维聚类分析，观察RTN1在不同种类免疫细胞的细胞聚类。使用TIMER在线工具分析预测TCGA队列肺腺癌患者免疫微环境中不同种类免疫细胞浸润丰度；使用TIMER和CIBERSORT研究与RTN1共表达基因和其相关肿瘤浸润免疫细胞之间的关系；最后，使用TIMER分析RTN1与免疫检查点之间的相关性。结果我们发现LUAD患者的RTN1表达降低，且与患者的预后密切相关。RTN1参与吞噬体的形成、造血细胞形成和细胞黏附的过程，对T细胞活化起着重要作用，使用cBioPortal与TCGA数据来分析，发现RTN1与BTK、CD4、ECSF1R、MNDA、NCKAP1L和SNX20显著相关。以上基因高表达可能会引起CD4+ T细胞、肥大细胞、单核细胞、髓样树突状细胞和M1型巨噬细胞显著上调。并且，RTN1表达与常见免疫检查点CD274、CTLA4、HAVCR2、LAG3、PDCD1、PDCD1LG2、TIGIT、SIGLEC15密切相关。结论RTN1作为一种肿瘤抑制基因并可能与更好的预后相关。此外，RTN1与可能参与免疫治疗反应的免疫浸润有关。但与其相关的机制需要进一步的研究。

CFTR reduces the proliferation of lung adenocarcinoma and is a strong predictor of survival in both smokers and non-smokers

BackgroundOne of the main hurdles of oncological therapy is the development of drug resistance. The ABC transporter gene family contributes majorly to cancer chemoresistance. However, effects of somatic expression of most ABC transporters on cancer outcomes remain largely unclear.MethodsWe systematically analyzed expression signatures of all 48 human ABC transporters in samples from 8562 patients across 14 different cancer types. The association between CFTR (ABCC7) expression and outcomes was analyzed experimentally using knock-downs and pharmacological CFTR stimulation.ResultsAcross 720 analyzed clinical associations with patient outcomes, 363 were nominally significant of which 29 remained significant after stringent Bonferroni correction. Among those were various previously known associations, as well as a multitude of novel factors that correlated with poor prognosis or predicted improved outcomes. The association between low CFTR levels and reduced survival in lung adenocarcinoma was confirmed in two independent cohorts of 246 patients with a history of smoking (logrank P = 0.0021, hazard ratio [HR], 0.49) and 143 never-smokers (logrank P = 0.0023, HR 0.31). Further in vitro experiments using naturally CFTR expressing lung adenocarcinoma cells showed that treatment with CFTR potentiators significantly reduced proliferation at therapeutically relevant concentrations.ConclusionsThese results suggest that CFTR acts as a pharmacologically activatable tumor suppressor and constitutes a promising target for adjuvant therapy in lung adenocarcinoma.

Abstract LB118: CEACAM7 as epigenetic prognostic marker in African Americans with lung adenocarcinoma

Abstract Background and Objectives of the Study: For the past several decades, lung cancer has had amongst the highest cancer incidence and mortality rates across the world. In the United States, African American (AA) individuals carry a disproportionate share of the lung cancer burden, with higher incidence, later-stage diagnosis, and poorer 5-year overall survival rate when compared with that of Whites. However, there is yet to be a race-specific biomarker for lung cancer. Most genomic data continue to include a small proportion of AA individuals, further contributing to the racial health disparity. Thus, the goal of our study was to conduct a genome-wide analysis to identify lung cancer biomarkers specific for AA individuals, to understand the role that these biomarkers play in overall survival, and to discover how epigenetic modulations may impact outcomes by race. Methods: We utilized clinical and genomic data from The Cancer Genome Atlas (TCGA) for lung adenocarcinoma (LUAD). We conducted a differential expression analysis to identify the differentially expressed genes (DEGs) amongst AA individuals compared with Whites with LUAD. Two-tailed log rank tests with univariate and multivariate Cox proportional hazard models adjusted by age, gender, prior malignancy and stage were used to analyze overall survival for mRNA expression and DNA methylation for each racial subgroup. We investigated the epigenetic modifications that are correlated with the expression of the DEGs that play a significant role in the survival of AA individuals with lung cancer. Results: CEACAM7 was the single gene that was both differentially expressed in AA individuals compared to Whites with LUAD and that had an impact on LUAD survival. CEACAM7 RNA expression showed trend towards significant direct correlation with LUAD stage in AA individuals but not for Whites. High RNA expression of CEACAM7 was associated with shorter median survival (P&amp;lt;0.0001) and increased mortality risk HR: 11.84, 95% CI: 2.69-52.17 for AA individuals with LUAD, but there were no differences in survival time or risk for Whites. We also identified 5 CpG probes inversely correlated with the expression of CEACAM7 (cg22895231, cg25465322, cg01656853, cg17659920, and cg07940585). Each one of them showed that low methylation values had significantly shorter overall median survival. Only cg01656853 and cg07940585 showed association between lower DNA methylation levels and increased mortality risk in multivariate COX regression models. Conclusion: This TCGA study suggests that the expression of CEACAM7 and its associated DNA methylation may play an important role in the survival of AA individuals with LUAD but not for Whites. Further studies are necessary to understand the mechanics of how the epigenetic regulation of CEACAM7 is associated with survival in AA individuals with LUAD and to identify new possible therapeutic targets. Citation Format: Richies Tiv, Ignacio Jusue-Torres, Apurva Mallisetty, Leglys Contreras-Vargas, Ludmila Danilova, Lawrence E. Feldman, Alicia Hulbert. CEACAM7 as epigenetic prognostic marker in African Americans with lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB118.

Long Non-Coding RNA-TMPO-AS1 as ceRNA Binding to let-7c-5p Upregulates STRIP2 Expression and Predicts Poor Prognosis in Lung Adenocarcinoma.

BackgroundStriatin-interacting protein 2 (STRIP2), also called Fam40b, has been reported to regulate tumor cell growth. But the role of STRIP2 in lung adenocarcinoma (LUAD) has not been discovered clearly. Thus, the aim of our study is to explore the function and underlying mechanism of STRIP2 in LUAD.MethodsExpression of STRIP2 was determined using the Cancer Genome Atlas (TCGA), GTEx, Ualcan, and the Human Protein Altas databases. The Correlation of STRIP2 and survival was detected by PrognoScan and Kaplan–Meier plotter databases. Besides, the correlation between STRIP2 expression and tumor immune infiltration as well as immune checkpoints were analyzed by the ssGSEA method. The biological function of STRIP2 and its co-expression genes was determined by gene ontology (GO) and Genes and Genomes (KEGG), respectively. Finally, the expression level and biological function of STRIP2 in LUAD were determined by qPCR, CCK8, transwell, and wound healing assays.ResultsThis manuscript revealed a significantly increased expression of mRNA and protein of STRIP2 in lung adenocarcinoma compared with the adjacent normal tissues. GEO and Kaplan–Meier plotter databases showed higher STRIP2 expression levels were correlated with poor prognosis survival of LUAD. Moreover, Cox regression analysis suggested that a higher STRIP2 level served as an independent risk factor in predicting deteriorative overall survival (OS) for LUAD patients. SsGSEA results showed STRIP2 expression level was positively correlated with infiltrating levels of Th2 cells in LUAD. Lastly, GO analysis indicated the biological processes were enriched in nuclear division and positive regulation of the cell cycle. KEGG signaling pathway analysis showed STRIP2 was correlated with the MAPK signaling pathway and the TNF signaling pathway. The GSEA database showed that STRIP2 was positively associated with the epithelial–mesenchymal transition, cell cycle, and TNF signaling pathway. The QRT-PCR assay showed that STRIP2 was upregulated in LUAD cell lines. Cell proliferation and migration were inhibited in LUAD by knockdown of STRIP2. Moreover, we confirmed that the TMPO-AS1/let-7c-5p/STRIP2 network regulates STRIP2 overexpression in LUAD and is associated with poor prognosis.ConclusionOur findings indicated that STRIP2 acted as a crucial oncogene in LUAD and was correlated with unfavorable survival and tumor infiltration inflation.

Integrative metabolomics and transcriptomics analysis reveals novel therapeutic vulnerabilities in lung cancer.

Non-small cell lung cancer (NSCLC) comprises the majority (~85%) of all lung tumors, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being the most frequently diagnosed histological subtypes. Multi-modal omics profiling has been carried out in NSCLC, but no studies have yet reported a unique metabolite-related gene signature and altered metabolic pathways associated with LUAD and LUSC. We integrated transcriptomics and metabolomics to analyze 30 human lung tumors and adjacent noncancerous tissues. Differential co-expression was used to identify modules of metabolites that were altered between normal and tumor. We identified unique metabolite-related gene signatures specific for LUAD and LUSC and key pathways aberrantly regulated at both transcriptional and metabolic levels. Differential co-expression analysis revealed that loss of coherence between metabolites in tumors is a major characteristic in both LUAD and LUSC. We identified one metabolic onco-module gained in LUAD, characterized by nine metabolites and 57 metabolic genes. Multi-omics integrative analysis revealed a 28 metabolic gene signature associated with poor survival in LUAD, with six metabolite-related genes as individual prognostic markers. We demonstrated the clinical utility of this integrated metabolic gene signature in LUAD by using it to guide repurposing of AZD-6482, a PI3Kβ inhibitor which significantly inhibited three genes from the 28-gene signature. Overall, we have integrated metabolomics and transcriptomics analyses to show that LUAD and LUSC have distinct profiles, inferred gene signatures with prognostic value for patient survival, and identified therapeutic targets and repurposed drugs for potential use in NSCLC treatment.

Prognostic Implication and Immunological Role of PSMD2 in Lung Adenocarcinoma.

Background: Although previous studies reported that 26S proteasome non-ATPase regulatory subunit 2 (PSMD2) is involved in many human cancers. However, its clinical significance and function in lung adenocarcinoma remain unclear. Here, we examined the prognostic and immunological role of PSMD2 in lung adenocarcinoma. Methods: The Cancer Genome Atlas (TCGA) was conducted to analyze PSMD2 expression and verified using UALCAN. PrognoScan and Kaplan-Meier curves were utilized to assess the effect of PSMD2 on survival. cBioPortal database was conducted to identify the mutation characteristics of PSMD2. Functional enrichment was performed to determine PSMD2-related function. Cancer Single-cell State Atlas (CancerSEA) was used to explore the cancer functional status of PSMD2 at single-cell resolution. PSMD2-related immune infiltration analysis was conducted. Tumor-Immune system interaction database (TISIDB) was performed to verify the correlation between PSMD2 expression and tumor-infiltrating lymphocytes (TILs). Results: Both mRNA and protein expression of PSMD2 were significantly elevated in lung adenocarcinoma. High expression of PSMD2 was significantly correlated with high T stage (p = 0.014), lymph node metastases (p < 0.001), and TNM stage p = 0.005). Kaplan-Meier curves indicated that high expression of PSMD2 was correlated with poor overall survival (38.2 vs. 59.7 months, p < 0.001) and disease-specific survival (59.9 months vs. not available, p = 0.004). Multivariate analysis suggested that PSMD2 was an independent biomarker for poor overall survival (HR 1.471, 95%CI, 1.024–2.114, p = 0.037). PSMD2 had a high mutation frequency of 14% in lung adenocarcinoma. The genetic mutation of PSMD2 was also correlated with poor overall survival, disease-specific survival, and progression-free survival in lung adenocarcinoma. Functional enrichment suggested PSMD2 expression was involved in the cell cycle, RNA transport, and cellular senescence. CancerSEA analysis indicated PSMD2 expression was positively correlated with cell cycle, DNA damage, and DNA repair. Immune infiltration analysis suggested that PSMD2 expression was correlated with immune cell infiltration levels and abundance of TILs. Conclusion: The upregulation of PSMD2 is significantly correlated with poor prognosis and immune infiltration levels in lung adenocarcinoma. Our findings suggest that PSMD2 is a potential biomarker for poor prognosis and immune therapeutic target in lung adenocarcinoma.

Image analysis reveals molecularly distinct patterns of TILs in NSCLC associated with treatment outcome

Despite known histological, biological, and clinical differences between lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), relatively little is known about the spatial differences in their corresponding immune contextures. Our study of over 1000 LUAD and LUSC tumors revealed that computationally derived patterns of tumor-infiltrating lymphocytes (TILs) on H&E images were different between LUAD (N = 421) and LUSC (N = 438), with TIL density being prognostic of overall survival in LUAD and spatial arrangement being more prognostically relevant in LUSC. In addition, the LUAD-specific TIL signature was associated with OS in an external validation set of 100 NSCLC treated with more than six different neoadjuvant chemotherapy regimens, and predictive of response to therapy in the clinical trial CA209-057 (n = 303). In LUAD, the prognostic TIL signature was primarily comprised of CD4+ T and CD8+ T cells, whereas in LUSC, the immune patterns were comprised of CD4+ T, CD8+ T, and CD20+ B cells. In both subtypes, prognostic TIL features were associated with transcriptomics-derived immune scores and biological pathways implicated in immune recognition, response, and evasion. Our results suggest the need for histologic subtype-specific TIL-based models for stratifying survival risk and predicting response to therapy. Our findings suggest that predictive models for response to therapy will need to account for the unique morphologic and molecular immune patterns as a function of histologic subtype of NSCLC.

Overexpression of ERCC6L correlates with poor prognosis and confers malignant phenotypes of lung adenocarcinoma.

Excision repair cross-complementation group 6 like (ERCC6L) has been reported to be upregulated in a variety of malignant tumors and plays a critical oncogenic role. However, the role and molecular mechanism of ERCC6L in lung adenocarcinoma (LUAD) remain unclear, and were therefore investigated in the present study. Clinical data of patients with LUAD were obtained and bioinformatics analysis was performed to investigate the expression characteristics, prognostic value, and biological function of ERCC6L. In addition, cell function experiments were performed to detect the effect of ERCC6L silencing on the biological behavior of LUAD cells. The results revealed that ERCC6L expression was significantly higher in LUAD tissues vs. normal lung tissues and closely associated with nodal invasion, advanced clinical stage and survival in LUAD. Overexpression of ERCC6L was an independent prognostic biomarker of overall survival, progression-free interval, and disease-specific survival in patients with LUAD. DNA amplification and low methylation levels of ERCC6L suggested regulation at both the genetic and epigenetic levels. The most significant positive genes co-expressed with ERCC6L were mainly enriched in the cell cycle signaling pathway. The major functions of ERCC6L in LUAD cells were positively correlated with the cell cycle, DNA damage, DNA repair, proliferation, invasion and epithelial-mesenchymal transition (EMT). Knockdown of ERCC6L inhibited the proliferative, migratory and invasive abilities of A549 and PC9 cells. It also promoted cell apoptosis, and led to cell cycle arrest in the S phase. ERCC6L may regulate the EMT process through the Wnt/β-catenin and Wnt/Notch 3 signaling pathways, thus regulating the tumorigenesis and progression of LUAD. The overexpression of ERCC6L may be a biological indicator for the diagnosis and prognosis of LUAD. ERCC6L may be a novel molecular target for the treatment of lung cancer.

Pan-cancer analysis of altered glycosyltransferases confers poor clinical outcomes.

Pan-cancer analysis of altered glycosyltransferases confers poor clinical outcomes.

Identification and Validation of lncRNA-SNHG17 in Lung Adenocarcinoma: A Novel Prognostic and Diagnostic Indicator.

BackgroundLung cancer has the highest death rate among cancers globally. Accumulating evidence has indicated that cancer-related inflammation plays an important role in the initiation and progression of lung cancer. However, the prognosis, immunological role, and associated regulation axis of inflammatory response-related gene (IRRGs) in non-small-cell lung cancer (NSCLC) remains unclear.MethodsIn this study, we perform comprehensive bioinformatics analysis and constructed a prognostic inflammatory response-related gene (IRRGs) and related competing endogenous RNA (ceRNA) network. We also utilized the Pearson’s correlation analysis to determine the correlation between IRRGs expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor-immune infiltration, and the drug sensitivity in NSCLC. Growth curve and Transwell assay used to verify the function of SNHG17 on NSCLC progression.ResultsFirst, we found that IRRGs were significantly upregulated in lung cancer, and its high expression was correlated with poor prognosis; high expression of IRRGs was significantly correlated with the tumor stage and poor prognosis in lung cancer patients. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated that these IRRGs are mainly involved in the inflammatory and immune response-related signaling pathway in the progression of NSCLC. We utilized 10 prognostic-related genes to construct a prognostic IRRGs model that could predict the overall survival of lung adenocarcinoma (LUAD) patients possessing high specificity and accuracy. Our evidence demonstrated that IRRGs expression was significantly correlated with the TMB, MSI, immune-cell infiltration, and diverse cancer-related drug sensitivity. Finally, we identified the upstream regulatory axis of IRRGs in NSCLC, namely, lncRNA MIR503HG/SNHG17/miR-330-3p/regulatory axis. Finally, knockdown of SNHG17 expression inhibited lung adenocarcinoma (LUAD) cell proliferation and migration. Our findings confirmed that SNHG17 is a novel oncogenic lncRNA and may be a biomarker for the prognosis and diagnosis of LUAD.ConclusionDNA hypomethylation/lncRNA MIR503HG/SNHG17/microRNA-330-3p/regulatory axis may be a valuable biomarker for prognosis and is significantly correlated with immune cell infiltration in lung cancer.

Clinicopathological characteristics and prognostic significance of HDAC11 protein expression in non-small cell lung cancer: a retrospective study.

BackgroundAlthough the prognosis of non-small cell lung cancer (NSCLC) can be assessed based on pathological type, disease stage and inflammatory indicators, the prognostic scoring model of NSCLC still needs to improve. HDAC11 is associated with poor prognosis of partial tumors, but its prognostic relationship with NSCLC is poorly understood. In this study, the role of HDAC11 in NSCLC was studied to evaluate relationship with disease prognosis and potential therapeutic target.MethodsThe clinicopathological and paracancerous tissues of patients with NSCLC primarily diagnosed in Tangdu Hospital from 2009 to 2013 were collected. Follow-up of patients were made every three months and the last follow-up period was December 2018. The expression of HDAC11 was assessed by immunohistochemistry (IHC). Then, weighted gene co-expression network analysis (WGCNA) was used to analyze the relationship between HDAC11 expression and the prognosis of lung adenocarcinoma (LUAD) patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Kaplan-Meier plotter database was used to verify the connection between hub genes and tumor stage and prognosis. We accessed the relationship between HDAC11 expression and clinicopathological features, and impact on the prognosis.ResultsThe study assessed 326 patients with NSCLC. Compared with adjacent tissues, HDAC11 expression was upregulated (HR =1.503, 95% CI: 1.172 to 1.927, P=0.001). Kaplan-Meier survival analyses showed that HDAC11 expression was closely related to OS of NSCLC patients (P=0.0011). Univariate and multivariate analyses showed that the independent risk factors of OS were clinical stage, HDAC11 expression, and HDAC11 differentiation (all P≤0.001). HDAC11 was significantly associated with prognosis in LUAD. A total of 1,174 differential genes and WGCNA were obtained to construct a co-expression network in LUAD. The GO and KEGG pathway enrichment analyses showed the relevance with staphylococcus aureus infection, NOD-like receptor signaling pathway, and others. The results of LUAD survival analysis showed that HDAC11-related genes NKX2-5 and FABP7 were significantly associated with LUAD prognosis.ConclusionsThe high expression of HDAC11 is related to the poor prognosis of LUAD, and it is expected to become a therapeutic target and prognostic evaluation therapy for LUAD in the future. However, the relevant results need to be further studied and verified.

Impact of sweet, umami, and bitter taste receptor (TAS1R and TAS2R) genomic and expression alterations in solid tumors on survival

Originally identified on the tongue for their chemosensory role, the receptors for sweet, umami, and bitter taste are expressed in some cancers where they regulate important cellular processes including apoptosis and proliferation. We examined DNA mutations (n = 5103), structural variation (n = 7545), and expression (n = 6224) of genes encoding sweet or umami receptors (TAS1Rs) and bitter receptors (TAS2Rs) in 45 solid tumors subtypes compared to corresponding normal tissue using The Cancer Genome Atlas and the Genotype Tissue Expression Project databases. Expression of TAS1R and TAS2R genes differed between normal and cancer tissue, and nonsilent mutations occurred in many solid tumor taste receptor genes (~ 1–7%). Expression levels of certain TAS1Rs/TAS2Rs were associated with survival differences in 12 solid tumor subtypes. Increased TAS1R1 expression was associated with improved survival in lung adenocarcinoma (mean survival difference + 1185 days, p = 0.0191). Increased TAS2R14 expression was associated with worse survival in adrenocortical carcinoma (−1757 days, p < 0.001) and esophageal adenocarcinoma (−640 days, p = 0.0041), but improved survival in non-papillary bladder cancer (+ 343 days, p = 0.0436). Certain taste receptor genes may be associated with important oncologic pathways and could serve as biomarkers for disease outcomes.

Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma.

Objective Recent studies have demonstrated that homeobox A1 (HOXA1) is upregulated in lung cancer due to RNA modifications (N6-methyladenosine), but the specific function of HOXA1 in lung adenocarcinoma (LUAD) remains indistinct. Herein, we investigated the role of HOXA1 in LUAD biology. Methods This study presented pancancer analysis of associations of HOXA1 with prognosis, TMB, and immune checkpoints. The expression of HOXA1 was detected in LUAD and normal tissues with immunohistochemistry and western blot. Through least absolute shrinkage and selection operator (LASSO) analysis, HOXA1-derived gene model was conducted in LUAD. Correlations of HOXA1 with immune cell infiltrations, immune checkpoints, HLAs, and chemotherapeutic sensitivity were evaluated. Colony formation, proliferation, and migration of LUAD cells with si-HOXA1 transfection were investigated, and the effects of HOXA1 on T cell exhaustion were assessed in vitro. Results HOXA1 expression was a risk factor of overall survival, disease-specific survival, and progression-free interval of LUAD. HOXA1 exhibited prominent associations with immune cell infiltration, immune checkpoints, and HLAs. HOXA1-derived gene signature reliably and independently predicted LUAD outcomes. Also, high-risk cases presented increased sensitivity to cisplatin, paclitaxel, docetaxel, vinorelbine, and etoposide. HOXA1 knockdown exhibited an inhibitory effect on proliferation and migration abilities of LUAD cells. Silencing HOXA1 weakened the expression of antioxidative stress markers Nrf2/HO-1 and T cell exhaustion marker CD155 in LUAD cells. Moreover, LUAD cells with HOXA1 knockdown enhanced the CD8+ T cell response. Conclusion Our data support the oncogenic function and prognostic significance of HOXA1 that facilitates immune escape and alleviates oxidative stress of LUAD.

LINC01426 Triggers Growth and Metastasis of Lung Adenocarcinoma as a Prognostic Indicator

The vital regulation of abnormally expressed lncRNAs in human cancers has been identified. This study is aimed at illustrating the role of LINC01426 in influencing malignant behaviors of lung adenocarcinoma (LUAD) and the possible mechanism. Differential expressions of LINC01426 in a downloaded profile containing LUAD and normal tissues were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA) database and were reconfirmed in clinical samples collected in our hospital. In addition, LINC01426 level in lung carcinoma cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR) as well. The relationship between LINC01426 expression and the age, tumor node metastasis (TNM) staging, lymphatic metastasis, tumor differentiation, and overall survival of LUAD was analyzed. After intervening LINC01426 level in H1299 and PC9 cells, proliferative and metastatic changes were assessed by functional experiments. LINC01426 was upregulated in LUAD tissues and cell lines. Its level was closely linked to TNM staging, lymphatic metastasis, tumor differentiation, and overall survival of LUAD. Knockdown of LINC01426 suppressed proliferative and metastatic abilities in H1299 and PC9 cells. LINC01246 is upregulated in LUAD samples and predicts a poor prognosis. It drives malignant process of LUAD via stimulating proliferative and metastatic abilities.