High O-linked N-acetylglucosamine transferase expression predicts poor survival in patients with early stage lung adenocarcinoma.
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ABSTRACT:
SUBMITTER: Lin YC
PROVIDER: S-EPMC6089550 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
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Project description:Background: The lung cancer staging system is insufficient for a comprehensive evaluation of patient prognosis. We constructed a novel immunoscore model to predict patients with high risk and poor survival. Method: Immunoscore was developed based on z-score transformed enrichment score of 11 immune-related gene sets of 109 immune risk genes. The immunoscore model was trained in lung adenocarcinoma cohort from The Cancer Genome Atlas (TCGA-LUAD) (n = 400), and validated in other two independent cohorts from Gene Expression Omnibus (GEO), GSE31210 (n = 219) and GSE68465 (n = 356). Meta-set (n = 975) was formed by combining all training and testing sets. Result: High immunoscore conferred worse prognosis in all sets. It was an independent prognostic factors in multivariate Cox analysis in training, testing and meta-set [hazard ratio (HR) = 2.96 (2.24-3.9), P < 0.001 in training set; HR = 1.99 (1.21-3.26), P = 0.006 in testing set 1; HR = 1.48 (1.69-2.39), P = 0.005 in testing set 2; HR = 2.01 (1.69-2.39), P < 0.001 in meta-set]. Immunoscore-clinical prognostic signature (ICPS) was developed by integrating immunoscore and clinical characteristic, and had higher C-index than immunoscore or stage alone in all sets [0.72 (ICPS) vs. 0.7 (immunoscore) or 0.59 (stage) in training set; 0.75 vs. 0.72 or 0.7 in testing set 1; 0.65 vs. 0.61 or 0.62 in testing set 2; 0.7 vs. 0.66 or 0.64 in meta-set]. Genome analysis revealed that immunoscore was positively correlated with tumor mutation burden (R = 0.22, P < 0.001). Besides, high immunoscore was correlated with high proportion of carcinoma-associated fibroblasts (R = 0.32, P < 0.001) in tumor microenvironment but fewer CD8+ cells infiltration (R = -0.28, P < 0.001). Conclusion: The immunoscore and ICPS are potential biomarkers for evaluating patient survival. Further investigations are required to validate and improve their prediction accuracy.
| S-EPMC7225293 | biostudies-literature
Project description:PURPOSE:The microRNA-34b/c (miR-34b/c) is considered a tumor suppressor in different tumor types and a transcriptional target of TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in patients with early-stage lung adenocarcinoma and to determine the functional role of miR-34b/c re-expression in lung adenocarcinoma cell lines. EXPERIMENTAL DESIGN:Aberrant methylation and expression of miR-34b/c were assessed in 15 lung adenocarcinoma cell lines and a cohort of 140 early-stage lung adenocarcinoma. Lung adenocarcinoma cell lines were transfected with miR-34b/c and the effects upon cell proliferation, migration, invasion, and apoptosis were investigated. RESULTS:Aberrant methylation of miR-34b/c was detected in 6 (40%) of 15 lung adenocarcinoma cell lines and 64 of 140 (46%) primary lung adenocarcinoma. Expression of miR-34b/c was significantly reduced in all methylated cell lines and primary tumors, especially with TP53 mutations. Patients with increased miR-34b/c methylation had significantly shorter disease-free and overall survival as compared to patients with unmethylated or low level of miR-34b/c methylation. Ectopic expression of miR-34b/c in lung adenocarcinoma cell lines decreased cell proliferation, migration, and invasion. CONCLUSIONS:Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in patients with early-stage lung adenocarcinoma. Reexpression of miR-34b/c leads to a less aggressive phenotype in lung adenocarcinoma cell lines.
| S-EPMC4161219 | biostudies-literature
Project description:BACKGROUND Lung adenocarcinoma (LUAD) is a type of non-small cell carcinoma. Its pathogenesis is being explored and there is no cure for the disease. MATERIAL AND METHODS The Gene Expression Omnibus (GEO) was searched to obtain data on expression of messenger RNA. GEO2R, an interactive web tool, was used to calculate the differentially expressed genes (DEGs) in LUAD. All the DEGs from different datasets were imported into VENNY 2.1 (https://bioinfogp.cnb.csic.es/tools/venny/index.html) to identify the intersection of the DEGs. An online analysis tool, the Database for Annotation, Visualization, and Integrated Discovery (DAVID), was used to help understand the biological meaning of DEG enrichment in LUAD. Cytoscape 3.7.2 was used to perform centrality analysis and visualize hub genes and related networks. Furthermore, the prognostic value of the hub genes was evaluated with the Kaplan-Meier plotter survival analysis tool. RESULTS The GEO database was used to obtain RNA sequencing information for LUAD and normal tissue from the GSE118370, GSE136043, and GSE140797 datasets. A total of 376 DEGs were identified from GSE118370, 248 were identified from GSE136403, and 718 DEGs were identified from GSE140797. The 10 genes with the highest degrees of expression - the hub genes - were CAV1, TEK, SLIT2, RHOJ, DGSX, HLF, MEIS1, PTPRD, FOXF1, and ADRB2. In addition, Kaplan-Meier survival evaluation showed that CAV1, TEK, SLIT2, HLF, MEIS1, PTPRD, FOXF1, and ADRB2 were associated with favorable outcomes for LUAD. CONCLUSIONS CAV1, TEK, SLIT2, HLF, MEIS1, PTPRD, FOXF1, and ADRB2 are hub genes in the DEG interaction network for LUAD and are involved in the development of and prognosis for the disease. The mechanisms underlying these genes should be the subject of further studies.
| S-EPMC8127640 | biostudies-literature
Project description:Cell division cycle associated 2(CDCA2) is overexpressed in neuroblastoma and oral squamous cell carcinoma, and its overexpression positively correlates to tumor progression. However, the biological and clinical significance of CDCA2 in lung adenocarcinoma(LAC) has never been investigated. We determined the expression profile and clinical significance of CDCA2 using The Cancer Genome Atlas(TCGA) and tissue microarray(TMA). Furthermore, we explored the biological function of CDCA2 both in vitro and in vivo. A great upregulation of CDCA2 was observed in LAC tissues compared with adjacent normal tissues. Importantly, Cox regression analysis indicated that high level of CDCA2 was an independent risk factor for overall survival(OS) in LAC patients (TCGA: HR = 1.720, p = 0.004; TMA: HR = 1.971, p = 0.023). Inhibition of CDCA2 suppressed the proliferation of LAC cells via G1 phase arrest by downregulating cyclin E1(CCNE1), while overexpression of CDCA2 promoted LAC cells proliferation by upregulating CCNE1. Moreover, the oncogenic activity of CDCA2 was also confirmed in vivo. In conclusion, CDCA2 promotes proliferation of LAC cells and predicts poor prognosis in LAC patients. CDCA2 might play a significant role in LAC progression.
| S-EPMC5386720 | biostudies-literature
Project description:Increasing evidence has revealed the significant association between dysregulated lncRNA expression and cancers. The prognostic value of lncRNAs in predicting the risk of disease recurrence and identifying high-risk subgroup of early stage lung adenocarcinoma (LUAD) is still unclear. In this study, we analyzed lncRNA expression profiles of 415 early-stage LUAD patients from Gene Expression Omnibus and identified a novel seven-lncRNA signature that was significantly associated with survival in patients with early-stage LUAD (HR = 2.718, CI = 2.054-3.597, p < 0.001). Based on the seven-lncRNA signature, we constructed a risk score model which is able to classify patients of training dataset into the high-risk group and the low-risk group with significantly different clinical outcome (p < 0.001). The robustness of the seven-lncRNA signature was successfully validated through application in other two independent patient datasets. Furthermore, the prognostic value of seven-lncRNA signature was independent of other clinicopathological factors including age, gender, stage and smoking status. Functional analysis suggested that the seven-lncRNA signature may be involved in a variety of biological pathways including cell cycle, ECM-receptor interaction, Focal adhesion and p53 signaling pathway. Taken together, our study not only provides insights into the lncRNA association with LUAD, but also provide alternative molecular markers in prognosis prediction for early-stage LUAD patients.
| S-EPMC5362451 | biostudies-literature
Project description:OBJECTIVES: Liver metastasis develops in 60% of patients after resection of pancreatic adenocarcinoma (PAC) and carries a dismal prognosis, but factors predictive of liver recurrence are poorly understood. Experimental evidence suggests that liver metastasis of PAC is mediated by CXCL12/CXCR4 signaling and can be inhibited by CXCR4 antagonist. We aimed to verify whether CXCR4 expression predicts early liver recurrence and poor survival after resection, and to explore the usefulness of CXCR4 status for prognosis prediction. METHODS: Ninety-seven consecutive PAC patients undergoing R0 resection were analyzed. CXCR4 expression was analyzed by immunohistochemistry, and its associations with liver recurrence-free survival and overall survival were analyzed by Kaplan-Meier estimates and multivariable Cox and accelerated failure time regression models. RESULTS: CXCR4-positive patients had a worse prognosis than CXCR4-negative patients, with a shorter liver recurrence-free survival (median: 8.7 vs. 39.7 months; P=0.004) and overall survival (median: 10.2 vs. 22.3 months; P<0.001). Overall survival for CXCR4-positive stage IIa patients was similar to that for stage IIb patients and significantly shorter than that for CXCR4-negative stage IIa patients (median: 9.7 vs. 27.4 months; P=0.002). CXCR4 positivity was significantly associated with liver recurrence (adjusted hazard ratio 2.22, 95% confidence interval (CI) 1.15-4.30; P=0.018) and predicted a 46% (95% CI 9-68%) and 35% (95% CI 7-54%) reduction in liver recurrence-free survival and overall survival, respectively. CONCLUSIONS: Tumor CXCR4 expression independently predicts early liver recurrence and poor overall survival after resection of PAC. CXCR4 status stratifies stage IIa patients into two groups with a striking difference in prognosis.
| S-EPMC3464805 | biostudies-other
Project description:PurposeRecent researches showed the vital role of BACH1 in promoting the metastasis of lung cancer. We aimed to explore the value of BACH1 in predicting the overall survival (OS) of early-stage (stages I-II) lung adenocarcinoma. Patients and Methods. Lung adenocarcinoma cases were screened from the Cancer Genome Atlas (TCGA) database. Functional enrichment analysis was performed to obtain the biological mechanisms of BACH1. Gene set enrichment analysis (GSEA) was performed to identify the difference of biological pathways between high- and low-BACH1 groups. Univariate and multivariate COX regression analysis had been used to screen prognostic factors, which were used to establish the BACH1 expression-based prognostic model in the TCGA dataset. The C-index and time-dependent AUC curve were used to evaluate predictive power of the model. External validation of prognostic value was performed in two independent datasets from Gene Expression Omnibus (GEO). Decision analysis curve was finally used to evaluate clinical usefulness of the BACH1-based model beyond pathologic stage alone.ResultsBACH1 was an independent prognostic factor for lung adenocarcinoma. High-expression BACH1 cases had worse OS. BACH1-based prognostic model showed an ideal C-index and t-AUC and validated by two GEO datasets, independently. More importantly, the BACH1-based model indicated positive clinical applicability by DCA curves.ConclusionOur research confirmed that BACH1 was an important predictor of prognosis in early-stage lung adenocarcinoma. The higher the expression of BACH1, the worse OS of the patients.
| S-EPMC8758312 | biostudies-literature
Project description:The discovery of Warburg effect opens a new era in anti-cancer therapy. Aerobic glycolysis is regarded as a hallmark of cancer cells and increasing literatures indicates that metabolic changes are critical for the maintenance and progression of cancer cells. Besides aerobic glycolysis, increased fatty acid synthesis is also required for the rapid growth of cancer cells, and is considered as one of the most typical metabolic symbols of cancer either. Thus, targeting fatty acid metabolism may provide a potential avenue for the diagnosis and therapeutic treatment of cancer. In this study, we have identified Sterol-CoA desaturase-1 (SCD1) which is the rate-limiting enzyme of unsaturated fatty acid synthesis, universally and highly expressed in lung adenocarcinoma and was required for the cell proliferation, migration and invasion. Both in vitro and in vivo studies demonstrated that high expression of SCD1 remarkably enhanced the ability of tumor formation and invasion, while knockdown of SCD1 significantly repressed tumorigenesis and induced cell apoptosis. Clinical association study suggested that high expression of SCD1 is more frequently observed in late stage patients and presents poor prognosis. Taken together, our results suggested that SCD1 is a potentially novel biomarker of lung adenocarcinoma, and targeting SCD1 may represent a new anti-cancer strategy.
| S-EPMC5129985 | biostudies-literature
Project description:Background: Topoisomerase IIA (TOP2A) gene encodes DNA topoisomerase enzyme and has been reported that TOP2A is broadly expressed in many types of cancers. Our study aims to investigate the prognostic effect of TOP2A on lung adenocarcinoma (LUAD) and the potential molecular mechanism of TOP2A to tumorigenesis. Methods: Bioinformatical analysis, real-time PCR and Western blot were applied to explore the expression level of TOP2A. Kaplan-Meier survival analysis was used to evaluate the effect of TOP2A on patients' prognosis. Cell proliferation, migration and invasion ability were examined by colony-formation, Cell Counting Kit-8 (CCK8) assay, wound healing assay and transwell invasion assay, respectively. Results: We firstly investigated differentially expressed genes in lung adenocarcinoma and normal tissues of GEO (tumor = 666, normal = 184) and TCGA (tumor = 517, normal = 59) and these data showed that TOP2A is broadly expressed in LUAD and the expression level of TOP2A is associated with poor prognosis, which indicated that TOP2A is an upregulated prognostic related gene in LUAD. Then we identified that the expression level of TOP2A was upregulated in both surgically removed lung cancer tissues and lung cancer cell lines. Knockdown of TOP2A in A549 and GLC82 cells inhibited cell proliferation, migration and invasion. Inhibition of TOP2A reduced the expression levels of CCNB1 and CCNB2, which indicated that TOP2A targeting CCNB1 and CCNB2 promotes GLC82 and A549 cells proliferation and metastasis. Conclusions: Our study revealed an important role of TOP2A in LUAD, and may provide a potential prognostic indicator and target for cancer therapy.
| S-EPMC7066024 | biostudies-literature
Project description:Background: Lung cancer is associated with the highest mortality rate of all cancer types, and the most common histologic subtype of lung cancer is adenocarcinoma. To apply more effective therapeutic treatment, molecular markers that are able to predict the recurrence risk of patients with adenocarcinoma are critically needed. Mutations in TP53 tumor suppressor gene have been found in approximately 50% of lung adenocarcinoma cases, but the presence of a TP53 mutation does not always associate with increased mortality.Methods: The Cancer Genome Atlas RNA sequencing data of lung adenocarcinoma were used to define a novel gene signature for P53 deficiency. This signature was then used to calculate a sample-specific P53 deficiency score based on a patient's transcriptomic profile and tested in four independent lung adenocarcinoma microarray datasets.Results: In all datasets, P53 deficiency score was a significant predictor for recurrence-free survival where high P53 deficiency score was associated with poor survival. The score was prognostic even after adjusting for several key clinical variables including age, tumor stage, smoking status, and P53 mutation status. Furthermore, the score was able to predict recurrence-free survival in patients with stage I adenocarcinoma and was also associated with smoking status.Conclusions: The P53 deficiency score was a better predictor of recurrence-free survival compared with P53 mutation status and provided additional prognostic values to established clinical factors.Impact: The P53 deficiency score can be used to stratify early-stage patients into subgroups based on their risk of recurrence for aiding physicians to decide personalized therapeutic treatment. Cancer Epidemiol Biomarkers Prev; 27(1); 86-95. ©2017 AACR.
| S-EPMC5839302 | biostudies-literature