Background: There is a rapid increase in lung adenocarcinomas (LUAD), and studies suggest associations between cuproptosis and the occurrence of various types of tumors. However, it remains unclear whether cuproptosis plays a role in LUAD prognosis.Methods: Dataset of the TCGA-LUAD was treated as training cohort, while validation cohort consisted of the merged datasets of the GSE29013, GSE30219, GSE31210, GSE37745, and GSE50081. Ten studied cuproptosis-related genes (CRG) were used to generated CRG clusters and CRG cluster-related differential expressed gene (CRG-DEG) clusters. The differently expressed lncRNA that with prognosis ability between the CRG-DEG clusters were put into a LASSO regression for cuproptosis-related lncRNA signature (CRLncSig). Kaplan–Meier estimator, Cox model, receiver operating characteristic (ROC), time-dependent AUC (tAUC), principal component analysis (PCA), and nomogram predictor were further deployed to confirm the model’s accuracy. We examined the model’s connections with other forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis. The immunotherapy ability of the signature was demonstrated by applying eight mainstream immunoinformatic algorithms, TMB, TIDE, and immune checkpoints. We evaluated the potential drugs for high risk CRLncSig LUADs. Real-time PCR in human LUAD tissues were performed to verify the CRLncSig expression pattern, and the signature’s pan-cancer’s ability was also assessed.Results: A nine-lncRNA signature, CRLncSig, was built and demonstrated owning prognostic power by applied to the validation cohort. Each of the signature genes was confirmed differentially expressed in the real world by real-time PCR. The CRLncSig correlated with 2,469/3,681 (67.07%) apoptosis-related genes, 13/20 (65.00%) necroptosis-related genes, 35/50 (70.00%) pyroptosis-related genes, and 238/380 (62.63%) ferroptosis-related genes. Immunotherapy analysis suggested that CRLncSig correlated with immune status, and checkpoints, KIR2DL3, IL10, IL2, CD40LG, SELP, BTLA, and CD28, were linked closely to our signature and were potentially suitable for LUAD immunotherapy targets. For those high-risk patients, we found three agents, gemcitabine, daunorubicin, and nobiletin. Finally, we found some of the CRLncSig lncRNAs potentially play a vital role in some types of cancer and need more attention in further studies.Conclusion: The results of this study suggest our cuproptosis-related CRLncSig can help to determine the outcome of LUAD and the effectiveness of immunotherapy, as well as help to better select targets and therapeutic agents.
BackgroundLung adenocarcinoma (LUAD) is the leading histological subtype of lung cancer worldwide, causing high mortality each year. The tumor immune cell infiltration (ICI) is closely associated with clinical outcome with LUAD patients. The present study was designed to construct a gene signature based on the ICI of LUAD to predict prognosis.MethodsDownloaded the raw data of three cohorts of the TCGA-LUAD, GSE72094, and GSE68465 and treat them as training cohort, validation cohort one, and validation cohort two for this research. Unsupervised clustering detailed grouped LUAD cases of the training cohort based on the ICI profile. The univariate Cox regression and Kaplan–Meier was adopted to identify potential prognostic genes from the differentially expressed genes recognized from the ICI clusters. A risk score-based prognostic signature was subsequently developed using LASSO-penalized Cox regression analysis. The Kaplan-Meier analysis, Cox analysis, ROC, IAUC, and IBS were constructed to assess the ability to predict the prognosis and effects of clinical variables in another two independent validation cohorts. More innovatively, we searched similar papers in the most recent year and made comprehensive comparisons with ours. GSEA was used to discover the related signaling pathway. The immune relevant signature correlation identification and immune infiltrating analysis were used to evaluate the potential role of the signature for immunotherapy and recognize the critical immune cell that can influence the signature's prognosis capability.ResultsA signature composed of thirteen gene including ABCC2, CCR2, CERS4, CMAHP, DENND1C, ECT2, FKBP4, GJB3, GNG7, KRT6A, PCDH7, PLK1, and VEGFC, was identified as significantly associated with the prognosis in LUAD patients. The thirteen-gene signature exhibited independence in evaluating the prognosis of LUAD patients in our training and validation cohorts. Compared to our predecessors, our model has an advantage in predictive power. Nine well know immunotherapy targets, including TBX2, TNF, CTLA4, HAVCR2, GZMB, CD8A, PRF1, GZMA, and PDCD1 were recognized correlating with our signature. The mast cells were found to play vital parts in backing on the thirteen-gene signature's outcome predictive capacity.ConclusionsCollectively, the current study indicated a robust thirteen-gene signature that can accurately predict LUAD prognosis, which is superior to our predecessors in predictive ability. The immune relevant signatures, TBX2, TNF, CTLA4, HAVCR2, GZMB, CD8A, PRF1, GZMA, PDCD1, and mast cells infiltrating were found closely correlate with the thirteen-gene signature's power.
Background Deacetylation of histones by histone deacetylase 3 (HDAC3) acts importantly in modulating apoptosis, DNA damage and cellular progression. Herein, we aimed to unravel the functional role of HDAC3 in a lethal disease, esophageal squamous cell carcinoma (ESCC). Methods The expression of HDAC3 in clinically collected ESCC tissues was determined by RT-qPCR and immunohistochemistry. As revealed from bioinformatics analysis, the putative relations between HDAC3 and microRNA-494 (miR-494) and between miR-494 and transforming growth factor beta (TGFβ)-inducing factor 1 (TGIF1) were further verified by chromatin immunoprecipitation and dual-luciferase reporter gene assay. Functional roles of shRNA-mediated depletion of HDAC3, miR-494 mimic and overexpressed TGIF1 were explored by gain- and loss-of-function assays with regard to ESCC cell biological behaviors. A nude mouse model of ESCC was developed for in vivo validation. Results HDAC3 was highly expressed in ESCC tissues, suggestive of poor prognosis while TGIF1 was upregulated and miR-494 was downregulated. Mechanistic investigation revealed that HDAC3 inhibited miR-494 expression and TGIF1 was a direct target of miR-494. Furthermore, silencing HDAC3 or overexpressing miR-494 was demonstrated to suppress aggressive phenotypes of ESCC cells both in vitro through the activated TGFβ signaling pathway and in vivo, while TGIF1 overexpression induced opposite results. Conclusion Collectively, our findings provided demonstration regarding the oncogenic property of HDAC3 in ESCC via the miR-494/TGIF1/TGFβ axis.
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