Identification of Ubiquitin-Related Gene-Pair Signatures for Predicting Tumor Microenvironment Infiltration and Drug Sensitivity of Lung Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC9317993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung adenocarcinoma (LUAD) has a high mortality rate and is difficult to diagnose and treat in its early stage. Previous studies have demonstrated that small nucleolar RNAs (snoRNAs) play a critical role in tumor immune infiltration and the development of a variety of solid tumors. However, there have been no studies on the correlation between tumor-infiltrating immune-related snoRNAs (TIISRs) and LUAD. In this study, we filtered six immune-related snoRNAs based on the tissue specificity index (TSI) and expression profile of all snoRNAs between all LUAD cell lines from the Cancer Cell Line Encyclopedia and 21 types of immune cells from the Gene Expression Omnibus database. Further, we performed real-time quantitative polymerase chain reaction (RT-qPCR) to validate the expression status of these snoRNAs on peripheral blood mononuclear cells (PBMCs) and lung cancer cell lines. Next, we developed a TIISR signature based on the expression profiles of snoRNAs from 479 LUAD patients filtered by the random survival forest algorithm. We then analyzed the value of this TIISR signature (TIISR risk score) for assessing tumor immune infiltration, immune checkpoint inhibitor (ICI) treatment response, and the prognosis of LUAD between groups with high and low TIISR risk score. Further, we found that the TIISR risk score groups showed significant differences in biological characteristics and that the risk score could be used to assess the level of tumor immune cell infiltration, thereby predicting prognosis and responsiveness to immunotherapy in LUAD patients.
| S-EPMC8649667 | biostudies-literature
Project description:Lung adenocarcinoma is often diagnosed at an advanced stage with poor prognosis. Patients with different clinical outcomes may have similar clinico-pathological characteristics. The results of previous studies for biomarkers for lung adenocarcinoma have generally been inconsistent and limited in clinical application. In this study, we used inverse-variance weighting to combine the hazard ratios for the four datasets and performed pathway analysis to identify prognosis-associated gene signatures. A total of 2,418 genes were found to be significantly associated with overall survival. Of these, a 21-gene signature in the HMGB1/RAGE signalling pathway and a 31-gene signature in the clathrin-coated vesicle cycle pathway were significantly associated with prognosis of lung adenocarcinoma across all four datasets (all p-values?<?0.05, log-rank test). We combined the scores for the three pathways to derive a combined pathway-based risk (CPBR) score. Three pathway-based signatures and CPBR score also had more predictive power than single genes. Finally, the CPBR score was validated in two independent cohorts (GSE14814 and GSE13213 in the GEO database) and had significant adjusted hazard ratios 2.72 (p-value?<?0.0001) and 1.71 (p-value?<?0.0001), respectively. These results could provide a more complete picture of the lung cancer pathogenesis.
| S-EPMC4455286 | biostudies-literature
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| S-EPMC10659611 | biostudies-literature
Project description:We profiled receptor tyrosine kinase pathway activation and key gene mutations in eight human lung tumor cell lines and 50 human lung tumor tissue samples to define molecular pathways. A panel of eight kinase inhibitors was used to determine whether blocking pathway activation affected the tumor cell growth. The HER1 pathway in HER1 mutant cell lines HCC827 and H1975 were found to be highly activated and sensitive to HER1 inhibition. H1993 is a c-MET amplified cell line showing c-MET and HER1 pathway activation and responsiveness to c-MET inhibitor treatment. IGF-1R pathway activated H358 and A549 cells are sensitive to IGF-1R inhibition. The downstream PI3K inhibitor, BEZ-235, effectively inhibited tumor cell growth in most of the cell lines tested, except the H1993 and H1650 cells, while the MEK inhibitor PD-325901 was effective in blocking the growth of KRAS mutated cell line H1734 but not H358, A549 and H460. Hierarchical clustering of primary tumor samples with the corresponding tumor cell lines based on their pathway signatures revealed similar profiles for HER1, c-MET and IGF-1R pathway activation and predict potential treatment options for the primary tumors based on the tumor cell lines response to the panel of kinase inhibitors.
| S-EPMC3200133 | biostudies-literature
Project description:The neutrophils exhibit both anti-tumor and pro-tumor effects in cancers. The correlation between neutrophils and tumor development in lung adenocarcinoma (LUAD) is still uncertain, possibly due to a lack of specific neutrophil infiltration evaluation methods. In this study, we identified 30 hub genes that were significantly associated with neutrophil infiltration in LUAD through data mining, survival analysis, and multiple tumor-infiltrating immune cells (TICs) analysis, including TIMER, CIBERSORT, QUANTISEQ, XCELL, and MCPCOUNTER. Consensus clustering analysis showed that these 30 hub genes were correlated with clinical features in LUAD. We further developed a neutrophil scoring system based on these hub genes. The neutrophil score was significantly correlated with prognosis and tumor immune microenvironment (TIME) in LUAD. It was also positively associated with PD-L1 expression and negatively associated with tumor mutational burden (TMB). When combined with the neutrophil score, the predictive capacity of PD-L1 and TMB for prognosis was significantly improved. Thus, the 30 hub genes might play an essential role in the interaction of neutrophils and LUAD, and the neutrophil scoring system might effectually assess the infiltration of neutrophils. Furthermore, we verified the expression of these 30 genes in the LUAD tumor tissues collected from our department. We further found that overexpressed TNFAIP6 and TLR6 and downregulated P2RY13, SCARF1, DPEP2, PRAM1, CYP27A1, CFP, GPX3, and NCF1 in LUAD tissue might be potentially associated with neutrophils pro-tumor effects. The following in vitro experiments demonstrated that TNFAIP6 and TLR6 were significantly overexpressed, and P2RY13 and CYP27A1 were significantly downregulated in LUAD cell lines, compared to BEAS-2B cells. Knocking down TNFAIP6 in A549 and PC9 resulted in the upregulation of FAS, CCL3, and ICAM-1, and the downregulation of CCL2, CXCR4, and VEGF-A in neutrophils when co-culturing with the conditioned medium (CM) from LUAD cells. Knocking down TNFAIP6 in LUAD also led to an elevated early apoptosis rate of neutrophils. Therefore, overexpressed TNFAIP6 in LUAD cancer cells might lead to neutrophils "N2" polarization, which exhibited pro-tumor effects. Further research based on the genes identified in this pilot study might shed light on neutrophils' effects on LUAD in the future.
| S-EPMC10777728 | biostudies-literature
Project description:Recently, several molecular subtypes with different prognosis have been found in lung adenocarcinoma (LUAD). However, the characteristics of the ferroptosis molecular subtypes and the associated tumor microenvironment (TME) cell infiltration have not been fully studied in LUAD. Using 1160 lung adenocarcinoma samples, we explored the molecular subtypes mediated by ferroptosis-related genes, along with the associated TME cell infiltration. The ferroptosis score was constructed using the least absolute shrinkage and selection operator regression (LASSO) method to quantify the ferroptosis characteristics of a single tumor. Three different molecular subtypes related to ferroptosis, with different prognoses, were identified in LUAD. Analysis of TME cell infiltration revealed immune heterogeneity among the three subtypes. Cluster A was characterized by immunosuppression and was associated with stromal activation. Cluster C was characterized by a large number of immune cells infiltrating the TME, promoting tumor immune response, and it was significantly enriched in immune activation-related signaling pathways. Relatively less infiltration of immune cells was a feature of cluster B. The ferroptosis score can predict tumor subtype, immunity and prognosis. A low ferroptosis score was characterized by immune activation and good prognosis, as seen in the cluster C subtype. Relative immunosuppression and poor prognosis were the characteristics of a high ferroptosis score, as seen in cluster A and B subtypes. At the same time, the anti-PD-1/L1 immunotherapy cohort demonstrated that a low ferroptosis score was associated with higher efficacy of immunotherapy. The ferroptosis score is a promising biomarker that could be of great significance to determine the prognosis, molecular subtypes, TME cell infiltration characteristics and immunotherapy effects in patients with LUAD.
| S-EPMC8437492 | biostudies-literature
Project description:BackgroundTUBA1C is a microtubule component that is involved in a variety of cancers. Our main objective was to investigate TUBA1C expression, its prognostic value, its potential biological functions, and its impact on the immune system of patients with lung adenocarcinoma (LUAD).MethodsThe Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA) and Immunohistochemistry Analysis were used to analyze TUBA1C expression, its clinicopathology, overall survival (OS), and disease-free survival (DFS) in LUAD patients. We also determined the correlation between TUBA1C and tumor-infiltrating immune cells (TIICs) by using CIBERSORT and GEPIA databases. To determine the expression of TUBA1C in LUAD, we analyzed a collection of immune infiltration levels and cumulative survival of LUAD tissues in TIMER database. By using UALCAN, STRING, and GeneMANIA databases, we investigated the protein-coding genes related to TUBA1C and its co-expression genes in LUAD tissues. Gene set enrichment analysis (GSEA) was performed by using the TCGA dataset.ResultsThe mRNA and the protein expression of TUBA1C were found to be up-regulated in LUAD tissues. The univariate analysis indicated that an increased expression of TUBA1C was significantly correlated to the following parameters: age, stage, and lymph node metastasis. An over-expression of TUBA1C was associated with a poor prognosis of LUAD. In TIMER and CIBERSORT databases, we found that TUBA1C is correlated with 13 types of TIICs: activated B cell, activated CD4 T cell, central memory CD4 T cell, effector memory CD8 T cell, eosinophils, immature B cell, gamma-delta T cell, immature dendritic cell, mast cell, memory B cell, natural killer T cell, regulatory T cell, and type 2T helper cell. By performing GSEA, we found that TUBA1C is closely correlated to cell cycle, p53 signaling pathway, glycolysis, and gluconeogenesis.ConclusionsOur findings indicate that TUBA1C is associated with TIICs in tumor microenvironment. Therefore, it serves as a novel prognostic biomarker and a target for future treatment methods of LUAD.
| S-EPMC7923461 | biostudies-literature
Project description:BackgroundThe incidence rate of lung adenocarcinoma (LUAD) is rapidly increasing. Recent studies have reported that histone acetylation modification plays an important role in the occurrence and development of tumors. However, the potential role of modification of histone acetylation modification in the development of tumor immune microenvironment is still unclear.MethodsIn this study, we comprehensively evaluated the acetylation modification patterns of LUAD samples obtained from various different databases based on 36 histone modification regulators, and constructed a prognostic model based on The Cancer Genome Atlas (TCGA) LUAD cohort using the Cox regression method. The close relationship between histone acetylation and tumor immune characteristics was further studied, including immune infiltration, immune escape and immunotherapy. Finally, we combined three cohort (GSE30219, GSE72094 and GSE50081) from Gene Expression Omnibus (GEO) database to verify the above results.ResultsWe analyzed the expression, mutation and interaction of 36 histone acetylation regulated genes. After Univariate Cox regression analysis and least absolute shrinkage and selection operator regression (LASSO), 5 genes (KAT2B, SIRT2, HDAC5, KAT8, HDAC2) were screened to establish the prognosis model and calculate the risk score. Then, patients in the TCGA cohort were divided into high- and low-risk groups based on the risk scores. Further analysis indicated that patients in the high-risk group exhibited significantly reduced overall survival (OS) compared with those in the low-risk group. The high- and low-risk groups exhibited significant differences in terms of tumor immune characteristics, such as immune infiltration, immune escape and immunotherapy. The high-risk group had lower immune score, less immune cell infiltration and higher clinical stage. Moreover, multivariate analysis revealed that this prognostic model might be a powerful prognostic predictor for LUAD. In addition, drugs sensitive for this classification were identified. Finally, the efficacy of the prognostic model was validated by cohort (GSE30219, GSE72094 and GSE50081) from GEO database.ConclusionsOur study provided a robust signature for predicting changing prognosis of patients with LUAD. Thus, it appears to be a potentially useful prognostic tool. Moreover, the important relationship between histone acetylation and tumor immune microenvironment was revealed.
| S-EPMC9641363 | biostudies-literature
Project description:Increasing studies have proved that malignant tumors are associated with energy metabolism. This study was aimed to explore biological variables that impact the prognosis of patients in the glycolysis-related subgroups of lung adenocarcinoma (LUAD). The mRNA expression profiling and mutation data in large LUAD samples were collected from the Cancer Genome Atlas (TCGA) database. Then, we identified the expression level and prognostic value of glycolysis-related genes, as well as the fractions of 22 immune cells in the tumor microenvironment. The differences between glycolysis activity, mutation, and immune infiltrates were discussed in these groups, respectively. Two hundred fifty-five glycolysis-related genes were identified from gene set enrichment analysis (GSEA), of which 43 genes had prognostic values (p < 0.05). Next, we constructed a glycolysis-related competing endogenous RNA (ceRNA) network which related to the survival of LUAD. Then, two subgroups of LUAD (clusters 1 and 2) were identified by applying unsupervised consensus clustering to 43 glycolysis-related genes. The survival analysis showed that the cluster 1 patients had a worse prognosis (p < 0.001), and upregulated differentially expressed genes (DEGs) are interestingly enriched in malignancy-related biological processes. The differences between the two subgroups are SPTA1, KEAP1, USH2A, and KRAS among top 10 mutated signatures, which may be the underlying mechanism of grouping. Combined high tumor mutational burden (TMB) with tumor subgroups preferably predicts the prognosis of LUAD patients. The CIBERSORT algorithm results revealed that low TMB samples were concerned with increased infiltration level of memory resting CD4+ T cell (p = 0.03), resting mast cells (p = 0.044), and neutrophils (p = 0.002) in cluster 1 and high TMB samples were concerned with increased infiltration level of memory B cells, plasma cells, CD4 memory-activated T cells, macrophages M1, and activated mast cells in cluster 2, while reduced infiltration of monocytes, resting dendritic cells, and resting mast cells was captured in cluster 2. In conclusion, significant different gene expression characteristics were pooled according to the two subgroups of LUAD. The combination of subgroups, TMB and tumor-infiltrating immune cell signature, might be a novel prognostic biomarker in LUAD.
| S-EPMC8339438 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) contains a variety of genomic and epigenomic abnormalities; the effective tumor markers related to these abnormalities need to be further explored.MethodsClustering analysis was performed based on DNA methylation (MET), DNA copy number variation (CNV), and mRNA expression data, and the differences in survival and tumor immune microenvironment (TIME) between subtypes were compared. Further, we evaluated the signatures in terms of both prognostic value and immunological characteristics.ResultsThere was a positive correlation between MET and CNV in LUAD. Integrative analysis of multi-omics data from 443 samples determined molecular subtypes, iC1 and iC2. The fractions of CD8+ T cells and activated CD4+ T cells were higher, the fraction of Tregs was lower, and the expression level of programmed death-ligand 1 (PD-L1) was higher in iC2 with a poor prognosis showing a higher TIDE score. We selected PTTG1, SLC2A1, and FAM83A as signatures of molecular subtypes to build a prognostic risk model and divided patients into high-risk group and low-risk group representing poor prognosis and good prognosis, respectively, which were validated in 180 patients with LUAD. Further, the low-risk group with lower TIDE score had more infiltrating immune cells. In 100 patients with LUAD, the high-risk group with an immunosuppressive state had a higher expression of PD-L1 and lower counts of CD8+ T cells and dendritic cells.ConclusionsThese findings demonstrated that combined multi-omics data could determine molecular subtypes with significant differences of prognosis and TIME in LUAD and suggested potent utility of the signatures to guide immunotherapy.
| S-EPMC8446514 | biostudies-literature