Expression and prognostic analyses of ITGA11, ITGB4 and ITGB8 in human non-small cell lung cancer.
ABSTRACT: Background:Integrins play a crucial role in the regulation process of cell proliferation, migration, differentiation, tumor invasion and metastasis. ITGA11, ITGB4 and ITGB8 are three encoding genes of integrins family. Accumulative evidences have proved that abnormal expression of ITGA11, ITGB4 and ITGB8 are a common phenomenon in different malignances. However, their expression patterns and prognostic roles for patients with non-small cell lung cancer (NSCLC) have not been completely illustrated. Methods:We investigated the expression patterns and prognostic values of ITGA11, ITGB4 and ITGB8 in patients with NSCLC through using a series of databases and various datasets, including ONCOMINE, GEPIA, HPA, TCGA and GEO datasets. Results:We found that the expression levels of ITGA11 and ITGB4 were significantly upregulated in both LUAD and LUSC, while ITGB8 was obviously upregulated in LUSC. Additionally, higher expression level of ITGB4 revealed a worse OS in LUAD. Conclusion:Our findings suggested that ITGA11 and ITGB4 might have the potential ability to act as diagnostic biomarkers for both LUAD and LUSC, while ITGB8 might serve as diagnostic biomarker for LUSC. Furthermore, ITGB4 could serve as a potential prognostic biomarker for LUAD.
Project description:The main non-small-cell lung cancer (NSCLC) histopathological subtypes are lung adenocarcinomas (LUAD) and lung squamous cell carcinomas (LUSC). To identify candidate progression determinants of NSCLC subtypes, we explored the transcriptomic signatures of LUAD versus LUSC. We then investigated the prognostic impact of the identified tumor-associated determinants. This was done utilizing DNA microarray data from 2,437 NSCLC patients. An independent analysis of a case series of 994 NSCLC was conducted by next-generation sequencing, together with gene expression profiling from GEO (https://www.ncbi.nlm.nih.gov/geo/). This work led us to identify 69 distinct tumor prognostic determinants, which impact on LUAD or LUSC clinical outcome. These included key drivers of tumor growth and cell cycle, transcription factors and metabolic determinants. Such disease determinants appeared vastly different in LUAD versus LUSC, and often had opposite impact on clinical outcome. These findings indicate that distinct tumor progression pathways are at work in the two NSCLC subtypes. Notably, most prognostic determinants would go inappropriately assessed or even undetected when globally investigating unselected NSCLC. Hence, differential consideration for NSCLC subtypes should be taken into account in current clinical evaluation procedures for lung cancer.
Project description:Different subtypes of non-small cell lung cancer (NSCLC) have distinct sites of origin, histologies, genetic and epigenetic changes. In this study, we explored the mechanisms of ECT2 dysregulation and compared its prognostic value in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In addition, we also investigated the enrichment of ECT2 co-expressed genes in KEGG pathways in LUAD and LUSC. Bioinformatic analysis was performed based on data from the Cancer Genome Atlas (TCGA)-LUAD and TCGA-LUSC. Results showed that ECT2 expression was significantly upregulated in both LUAD and LUSC compared with normal lung tissues. ECT2 expression was considerably higher in LUSC than in LUAD. The level of ECT2 DNA methylation was significantly lower in LUSC than in LUAD. ECT2 mutation was observed in 5% of LUAD and in 51% of LUSC cases. Amplification was the predominant alteration. LUAD patients with ECT2 amplification had significantly worse disease-free survival (p = 0.022). High ECT2 expression was associated with unfavorable overall survival (OS) (p<0.0001) and recurrence-free survival (RFS) (p = 0.001) in LUAD patients. Nevertheless, these associations were not observed in patients with LUSC. The following univariate and multivariate analysis showed that the high ECT2 expression was an independent prognostic factor for poor OS (HR: 2.039, 95%CI: 1.457-2.852, p<0.001) and RFS (HR: 1.715, 95%CI: 1.210-2.432, p = 0.002) in LUAD patients, but not in LUSC patients. Among 518 genes co-expressed with ECT2 in LUAD and 386 genes co-expressed with ECT2 in LUSC, there were only 98 genes in the overlapping cluster. Some of the genes related KEGG pathways in LUAD were not observed in LUSC. These differences might help to explain the different prognostic value of ECT2 in LUAD and LUSC, which are also worthy of further studies.
Project description:Emerging evidences demonstrate that circular RNAs (circRNAs) are abnormally expressed in tumors and could serve as prognostic markers for cancers. However, the expression patterns and clinical implications of circRNAs in non-small cell lung cancer (NSCLC) remain obscure. In this study, we profiled circRNA expressions in 10 pairs of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) after ribosomal RNA-depletion and RNase R digestion to enrich circRNAs. Combining five circRNA computational programs, we found that LUAD and LUSC not only share common expression patterns, but also exhibit distinct circRNA expression signatures. Moreover, the Receiver Operating Characteristic (ROC) curve analysis indicated that hsa_circ_0077837 and hsa_circ_0001821 could serve as potential biomarkers for both LUAD and LUSC, while hsa_circ_0001073 and hsa_circ_0001495 could be diagnostic/subtyping marker for LUAD and LUSC, respectively. Therefore, our findings highlight the important diagnostic potential of circRNAs in NSCLC.
Project description:Background:Lung cancer is the most malignant tumor with the highest morbidity and mortality. This study aimed to investigate the role of the expression and the significance of the p42.3 gene in non-small cell lung cancer (NSCLC). Methods:Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were analyzed based on the biological information data of The Cancer Genome Atlas (TCGA). Furthermore, 142 postoperative tumor tissue and normal tissue samples (70 cases of LUAD and 72 cases of LUSC) from NSCLC patients admitted to our hospital from 2005 to 2009 were retrospectively collected. Paraffin-embedded tissues were used to make the tissue microarrays (TMA), and the expression of the p42.3 protein was detected by immunohistochemical staining. Results:The expression of p42.3 in both LUAD and LUSC was significantly upregulated (P<0.01) compared with the normal lung tissues. The p42.3 expression was significantly higher than that of LUAD (P<0.01) in the LUSC group. LUSC had a lower level of p42.3 DNA methylation and a higher level of p42.3 DNA amplification than LUAD. The expression rate of p42.3 protein decreased in patients 70 years or older (P=0.029). High expression of the p42.3 protein was an independent factor for worse pathological differentiation (P=0.043). Conclusions:Both genetic and epigenetic alterations contributed to dysregulated p42.3 in NSCLC. Despite the temporary absence of TCGA-LUSC (TCGA data on LUSC) survival information, we observed that the up-regulated expression of p42.3 in LUSC was significantly higher than that in LUAD by analyzing the public database and reviewing the real-world data. Furthermore, a high expression of p42.3 protein was significantly correlated with poor differentiation of tumor tissues. Therefore, the prognostic value of p42.3 in LUSC deserves further study.
Project description:Golgi membrane protein 1 (GOLM1) is a transmembrane glycoprotein of the Golgi cisternae, which is implicated in carcinogenesis of multiple types of cancer. In this study, using data from the Gene Expression Omnibus and The Cancer Genome Atlas, we compared the expression of GOLM1 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and studied its prognostic value in terms of overall survival (OS) and recurrence-free survival (RFS) in these 2 subtypes of non-small cell lung cancer (NSCLC). Results showed that GOLM1 was significantly upregulated in both LUAD and LUSC tissues compared to the normal controls. However, GOLM1 expression was higher in LUAD tissues than in LUSC tissues. More importantly, using over 10 years' survival data from 502 patients with LUAD and 494 patients with LUSC, we found that high GOLM1 expression was associated with unfavorable OS and RFS in patients with LUAD, but not in patients with LUSC. The following univariate and multivariate analyses confirmed that increased GOLM1 expression was an independent prognostic indicator of poor OS (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.11-1.54, P = .002) and RFS (HR: 1.37, 95% CI: 1.14-1.64, P = .001) in patients with LUAD. Of 511 cases with LUAD, 248 (48.5%) had heterozygous loss (-1), while 28 (5.5%) of 511 cases with LUAD had low-level copy gain (+1). In addition, we also found that the methylation status of 1 CpG site (chr9: 88,694,942-88,694,944) showed a weak negative correlation with GOLM1 expression (Pearson r = -0.25). Based on these findings, we infer that GOLM1 might serve as a valuable prognostic biomarker in LUAD, but not in LUSC. In addition, DNA copy number alterations and methylation might be 2 important mechanisms of dysregulated GOLM1 in LUAD.
Project description:Previous studies have demonstrated that the interleukin (IL)-6/ IL-6 receptor (IL-6R) signaling pathway contributes to the pathogenesis of lung cancer. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two major pathological subtypes of non-small cell lung cancer (NSCLC). The present study aimed to elucidate the potential clinical prognosis and biological function of IL-6R mRNA expression in LUAD and LUSC. The search term 'lung cancer' was used to search through the Gene Expression Omnibus database. Including LUAD and LUSC datasets in The Cancer Genome Atlas database, a total of 8 LUAD and 6 LUSC datasets were included in the present analysis. It was observed that a higher expression level of IL-6R mRNA in tumor tissues was a significant positive prognostic factor for overall survival in LUAD [pooled hazard ratio (HR), 0.48 and P<0.001 for univariate analysis; pooled HR, 0.50 and P<0.001 for multivariate analysis] while there was no similar association in LUSC (pooled HR, 1.59 and P=0.062 for univariate analysis; pooled HR, 1.58 and P=0.079 for multivariate analysis). Correlation analysis revealed that IL-6 and IL-6R were negatively correlated in LUAD and positively correlated in LUSC. IL-6R and its most correlated genes were primarily involved in cell cycle progression in LUAD and primarily involved in tumor angiogenesis, invasion and metastasis in LUSC. These results suggest a possible role of tumoral expression for IL-6R in LUAD, which means it may have potential as a prognostic marker for this type of cancer.
Project description:Among early?stage non?small?cell lung cancer (NSCLC) patients, cg05293407TRIM27 was significantly and exclusively associated with survival of lung squamous cell carcinoma patients, who had higher smoking intensity compared to lung adenocarcinoma patients. Generally, the significant association between cg05293407TRIM27 and survival only remained in NSCLC patients having medium?to?high pack?year of smoking. The cg05293407TRIM27?smoking synergistic interaction might account for histologically heterogeneous effects of TRIM27 DNA methylation on NSCLC survival. Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non?small?cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early?stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30–2.09, P = 4.52 × 10?5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87–1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407TRIM27 methylation in NSCLC. LUSC patients had a higher average pack?year of smoking (37.49LUAD vs 54.79LUSC, P = 1.03 × 10?19) and included a higher proportion of current smokers than LUAD patients (28.24%LUAD vs 34.09%LUSC, P = 0.037). cg05293407TRIM27 was significantly associated with overall survival only in NSCLC patients with medium–high pack?year of smoking (HR = 1.58, 95% CI: 1.26–1.96, P = 5.25 × 10?5). We conclude that cg05293407TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.
Project description:Non-small cell lung cancer (NSCLC), which consists mainly of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), are the leading cause of cancer deaths worldwide. In this study, we performed a comprehensive analysis of the tumor microenvironmental and genetic factors to identify prognostic biomarkers for NSCLC. We evaluated the immune and stromal scores of patients with LUAD and LUSC using data from The Cancer Genome Atlas database with the ESTIMATE algorithm. Based on these scores, the differentially expressed genes were obtained and immune-related prognostic genes were identified. Functional analysis and protein-protein interaction network further revealed the immune-related biological processes in which these genes participated. Additionally, 22 subsets of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment were analyzed with the CIBERSORT algorithm. Finally, we validated these valuable genes using an independent cohort from the Gene Expression Omnibus database. The associations of the immune and stromal scores with patients' clinical characteristics and prognosis were positive in LUAD but negative in LUSC and the correlations of TIICs with clinical characteristics were clarified. Several differentially expressed genes were identified to be potential immune-related prognostic genes. This study comprehensively analyzed the tumor microenvironment and presented immune-related prognostic biomarkers for NSCLC.
Project description:The tumor microenvironment consists of an intricately organized system through which immune cells and cancer cells may communicate to regulate anti-tumor immunogenicity. To this end, non-small cell lung cancer (NSCLC) has been shown to activate a variety of immunological mechanisms, thereby broadening our understanding of lung cancer immunobiology. However, while recent work has highlighted the importance of NSCLC immunology and prognosis, studies have not yet examined the tumor microenvironment (TME) globally in regards to the survival outcomes between two major NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In the present study, we identify an immunogenic tumor microenvironment state in NSCLC that is enriched for the lung adenocarcinoma subtype. By utilizing TME cell enrichment scores and RNA-seq expression data, we show that the inflamed TME is associated with favorable patient survival in lung adenocarcinoma, but this does not hold true for lung squamous cell carcinoma. Moreover, differentially regulated pathways between immune-inflamed and immune-excluded tumors within LUAD and LUSC were not subtype specific. Instead, immune-inflamed LUSC samples possessed elevated immune checkpoint marker expression when compared to those of the LUAD samples, thereby offering a putative explanation for our prognostic observations. These results shed light on the immunological prognostic effects within lung cancer and may encourage further TME exploration between these two subtypes as the landscape of NSCLC therapy progresses.
Project description:Introduction: Accumulating evidence showed that a large number of microRNAs (miRNAs) are abnormally expressed in lung cancer tissues and play critical roles in cancer development and progression. The aim of this study is to identify the differentially expressed miRNAs (DEMs) between non-small cell lung cancer (NSCLC) and normal lung tissues, and evaluate the prognostic value and potential target gene functional enrichment of the DEMs. Materials and Methods: We first downloaded the high-throughput miRNA data from The Cancer Genome Atlas Project (TCGA) database, and subsequently analyzed the data using bioinformatics analysis including limma package in R, Kaplan-Meier curve and Log-rank method, and several online analysis tools. Results: A total of 125 DEMs and 138 DEMs were respectively identified in lung adenocarcinoma (LUAD) tissues and lung squamous cell carcinoma (LUSC) tissues compared with their matched normal tissues. Moreover, we found that the prognostic function of the eight miRNAs (miR-375, miR-148a, miR-29b-1 and miR-584 for LUAD; miR-4746, miR-326, miR-93 and miR-671 for LUSC). Furthermore, the two four-miRNA signatures were constructed and found to be an independent prognostic factor for LUAD and LUSC patients, respectively. Additionally, our results indicated that the target genes of eight miRNAs may be involved in various pathways related to NSCLC, including PI3K-Akt, TGF-beta, FoxO, Ras, GPI-anchor biosynthesis and metabolic, Rap1, HIF-1 and proteasome. Conclusion: Overall, eight miRNAs were closely correlated with survival of NSCLC patients, and the constructed two four-miRNA signatures could be respectively used as prognostic markers in LUAD and LUSC patients.