SCD1 is associated with tumor promotion, late stage and poor survival in lung adenocarcinoma.
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ABSTRACT:
SUBMITTER: Huang J
PROVIDER: S-EPMC5129985 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:The cyclin-dependent kinase inhibitor 3 (CDKN3) has been perceived as a tumour suppressor. Paradoxically, CDKN3 is often overexpressed in human cancer. It was unclear if CDKN3 overexpression is linked to alternative splicing variants or mutations that produce dominant-negative CDKN3.We analysed CDKN3 expression and its association with patient survival in three cohorts of lung adenocarcinoma. We also examined CDKN3 mutations in the Cancer Genome Atlas (TCGA) and the Moffitt Cancer Center's Total Cancer Care (TCC) projects. CDKN3 transcripts were further analysed in a panel of cell lines and lung adenocarcinoma tissues. CDKN3 mRNA and protein levels in different cell cycle phases were examined.CDKN3 is overexpressed in non small cell lung cancer. High CDKN3 expression is associated with poor overall survival in lung adenocarcinoma. Two CDKN3 transcripts were detected in all samples. These CDKN3 transcripts represent the full length CDKN3 mRNA and a normal transcript lacking exon 2, which encodes an out of frame 23-amino acid peptide with little homology to CDKN3. CDKN3 mutations were found to be very rare. CDKN3 mRNA and protein were elevated during the mitosis phase of cell cycle.CDKN3 overexpression is prognostic of poor overall survival in lung adenocarcinoma. CDKN3 overexpression in lung adenocarcinoma is not attributed to alternative splicing or mutation but is likely due to increased mitotic activity, arguing against CDKN3 as a tumour suppressor.
| S-EPMC4701993 | 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:Tumor cell heterogeneity can make selection of appropriate interventions to lung cancer a challenge. Novel biomarkers predictive of disease risk and treatment response are needed to improve personalized treatment strategies. O-GlcNAcylation, the attachment of ?-N-acetylglucosamine (O-GlcNAc) to serine or threonine residues of intracellular proteins, modulates protein functions and is implicated in cancer pathogenesis. O-GlcNAc-transferase (OGT) and O-GlcNAcase (OGA) catalyze O-GlcNAc addition and removal, respectively. We used immunohistochemistry to explore the utility of OGT, OGA, and O-GlcNAc as potential biomarkers for lung adenocarcinoma. We found that high OGT expression is associated with poor overall survival (OS) in both stage I patients (P=0.032) and those at variable stages of disease (P=0.029), and with poor recurrence-free survival (RFS) in stage I patients (P=0.035). High OGT expression is also associated with poorer OS in patients with EGFR wild-type tumors at variable stages (P=0.038). Multivariate analysis indicated that OGT expression is an independent prognostic factor for RFS (HR 2.946, 95% CI: 1.411-6.150, P=0.004) and OS (HR 2.002, 95% CI: 1.183-3.391, P=0.010) in stage I patients. Our findings indicate OGT is a promising biomarker for further classifying early stage lung adenocarcinomas.
| S-EPMC6089550 | 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:CUE domain-containing 2 (CUEDC2) is a multi-functional protein, which regulates cell cycle, growth factor signaling and inflammation. We found that CUEDC2 was low in lung adenocarcinoma cell lines and lung adenocarcinoma tissues at both mRNA and protein levels. Low levels of CUEDC2 were correlated with a shorter survival time in patients with lung adenocarcinoma (p = 0.004). CUEDC2 expression was correlated with tumor T classification (P = 0.001) at clinical stage (P = 0.001) and tumor size (P = 0.033). Multivariate analysis suggested that CUEDC2 expression is an independent prognostic indicator for patients with lung adenocarcinoma. Ectopic expression of CUEDC2 decreased cell proliferation in vitro and inhibited tumor growth in nude mice in vivo. Knockdown of endogenous CUEDC2 by short hairpin RNAs (shRNAs) increased tumor growth. Inhibition of proliferation by CUEDC2 was associated with inactivation of the PI3K/Akt pathway, induction of p21 and down-regulation of cyclin D1. Our results suggest that decreased expression of CUEDC2 contributes to tumor growth in lung adenocarcinoma, leading to a poor clinical outcome.
| S-EPMC4653035 | biostudies-literature
Project description:Microtubule-associated tumor suppressor 1 (MTUS1) is thought to be downregulated in arious human cancers, which suggests its role as a tumor suppressor. This study investigated the clinicopathological significance of MTUS1 expression in lung adenocarcinoma. Tissue microarray blocks consisting of 161 cases were constructed, and immunohistochemical staining was used to assess MTUS1 expression. Correlations of MTUS1 expression and clinicopathological parameters were analyzed. In addition, we used public databases and performed bioinformatics analysis. Low level of MTUS1 was significantly associated with higher clinical stage (p = 0.006), higher tumor stage (p = 0.044), lymph node metastasis (p = 0.01), worse histologic grade (p = 0.007), lymphovascular invasion (p = 0.014), and higher Ki-67 proliferation index (p < 0.001). Patients with low MTUS1 expression also showed shorter disease-free survival (p = 0.002) and cancer-specific survival (p = 0.006). Analysis of data from the Cancer Genome Atlas confirmed that the mRNA expression of MTUS1 in lung adenocarcinoma was significantly lower than that of normal lung tissue (p = 0.02), and patients with decreased MTUS1 expression showed significantly shorter overall survival (p = 0.008). These results suggest that MTUS1 may be a potential biomarker for predicting clinical outcomes in lung adenocarcinoma patients.
| S-EPMC8306423 | biostudies-literature
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:BackgroundDue to the relatively insidious early symptoms of lung adenocarcinoma (LUAD), most LUAD patients are at an advanced stage at the time of diagnosis and lose the best chance of surgical resection. Mounting evidence suggested that the tumor microenvironment (TME) was highly correlated with tumor occurrence, progress, and prognosis. However, TME in advanced LUAD remained to be studied and reliable prognostic signatures based on TME in advanced LUAD also had not been well-established. This study aimed to understand the cell composition and function of TME and construct a gene signature associated with TME in advanced LUAD.MethodsThe immune, stromal, and ESTIMATE scores of each sample from The Cancer Genome Atlas (TCGA) database were, respectively, calculated using an ESTIMATE algorithm. The LASSO and Cox regression model were applied to select prognostic genes and to construct a gene signature associated with TME. Two independent datasets from the Gene Expression Omnibus (GEO) were used for external validation. Twenty-two subsets of tumor-infiltrating immune cells (Tiics) were analyzed using the CIBERSORT algorithm.ResultsFavorable overall survival (OS) and progression-free survival (PFS) were found in patients with high immune score (p = 0.048 and p = 0.028; respectively) and stromal score (p = 0.024 and p = 0.025; respectively). Based on the immune and stromal scores, 453 differentially expressed genes (DEGs) were identified. Using the LASSO and Cox regression model, a seven-gene signature containing AFAP1L2, CAMK1D, LOXL2, PIK3CG, PLEKHG1, RARRES2, and SPP1 was identified to construct a risk stratification model. The OS and PFS of the high-risk group were significantly worse than that of the low-risk group (p < 0.001 and p < 0.001; respectively). The receiver operating characteristic (ROC) curve analysis confirmed the good potency of the seven-gene signature. Similar findings were validated in two independent cohorts. In addition, the proportion of macrophages M2 and Tregs was higher in high-risk patients (p = 0.041 and p = 0.022, respectively).ConclusionOur study established and validated a seven-gene signature associated with TME, which might serve as a prognosis stratification tool to predict survival outcomes of advanced LUAD patients. In addition, macrophages M2 polarization may lead to worse prognosis in patients with advanced LUAD.
| S-EPMC8450538 | biostudies-literature
Project description:BACKGROUND:The major pathological type of non-small cell lung cancer is lung adenocarcinoma (LAC), which has a poor prognosis. BRCA1-associated protein-1 (BAP1) is a newly identified tumor suppressor that regulates a number of cellular functions in somatic malignancies. However, the impact of BAP1 expression in LAC has not been investigated. METHODS:A total of 112 cases of LAC and 101 cases of non-neoplastic lung diseases were included in this study. The study focused on BAP1 expression in lung tissues and its relationship to patients' clinical and pathological features. BAP1 expression was detected by immunohistochemistry. A human LAC cell line NCI-H1299 was transfected with lipofectamine p3xFLAG-BAP1. BAP1 gene expression was silenced in another LAC cell line NCI-H1650, in order to test the inhibitory effect of BAP1 on cell migration and invasion, as well as cell cycle regulation. RESULTS:BAP1 expression showed a negative correlation with tumorigenesis of LAC (p <0.001) and lymph node metastasis (p?=?0.010). High expression of BAP1 predicted longer disease free survival (p?=?0.040) and overall survival (p?=?0.021) of LAC patients. In functional assays, BAP1 was found to inhibit the migration and invasion of LAC cells, and promoted their apoptosis and necrosis. CONCLUSIONS:We identify BAP1 as a LAC precursor as well as a robust prognostic indicator in LAC patients. This study provides in vitro rationale for the further investigation of BAP1 in preclinical studies.
| S-EPMC4994180 | biostudies-literature