The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the c...The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the clinic.It has been shown that microRNAs(miRNAs)play a significant role in tumor chemoresistance.In this study,miR-125b was identified as a specific cisplatin(DDP)-resistant gene in LUAD,as indicated by the bioinformatics analysis and the real-time quantitative PCR assay.The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time.MiR-125b decreased the A549/DDP proliferation,and the multiple drug resistance-and autophagy-related protein expression levels,which were all reversed by the inhibition of miR-125b.In addition,xenografts of human tumors in nude mice were suppressed by miR-125b,demonstrating that through autophagy regulation,miR-125b could reverse the DDP resistance in LUAD cells,both in vitro and in vivo.Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L,which in turn inhibited autophagy and reversed chemoresistance.Based on these findings,miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.展开更多
Advanced LUAD shows limited response to treatment including immune therapy.With the development of sequencing omics,it is urgent to combine high-throughput multi-omics data to identify new immune checkpoint therapeuti...Advanced LUAD shows limited response to treatment including immune therapy.With the development of sequencing omics,it is urgent to combine high-throughput multi-omics data to identify new immune checkpoint therapeutic response markers.Using GSE72094(n=386)and GSE31210(n=226)gene expression profile data in the GEO database,we identified genes associated with lung adenocarcinoma(LUAD)death using tools such as“edgeR”and“maftools”and visualized the characteristics of these genes using the“circlize”R package.We constructed a prognostic model based on death-related genes and optimized the model using LASSO-Cox regression methods.By calculating the cell death index(CDI)of each individual,we divided LUAD patients into high and low CDI groups and examined the relationship between CDI and overall survival time by principal component analysis(PCA)and Kaplan-Meier analysis.We also used the“ConsensusClusterPlus”tool for unsupervised clustering of LUAD subtypes based on model genes.In addition,we collected data on the expression of immunomodulatory genes and model genes for each cohort and performed tumor microenvironment analyses.We also used the TIDE algorithm to predict immunotherapy responses in the CDI cohort.Finally,we studied the effect of PRKCD on the proliferation and migration of LUAD cells through cell culture experiments.The study utilized the TCGA-LUAD cohort(n=493)and identified 2,901 genes that are differentially expressed in patients with LUAD.Through KEGG and GO enrichment analysis,these genes were found to be involved in a wide range of biological pathways.The study also used univariate Cox regression models and LASSO regression analyses to identify 17 candidate genes that were best associated with mortality prognostic risk scores.By comparing the overall survival(OS)outcomes of patients with different CDI values,it was found that increased CDI levels were significantly associated with lower OS rates.In addition,the study used unsupervised cluster analysis to divide 115 LUAD patients into two distinct clusters with significant differences in OS timing.Finally,a prognostic indicator called CDI was established and its feasibility as an independent prognostic indicator was evaluated by Cox proportional risk regression analysis.The immunotherapy efficacy was more sensitive in the group with high expression of programmed cell death models.Relationship between programmed cell death(PCD)signature models and drug reactivity.After evaluating the median inhibitory concentration(IC50)of various drugs in LUAD samples,statistically significant differences in IC50 values were found in cohorts with high and low CDI status.Specifically,Gefitinib and Lapatinib had higher IC50 values in the high-CDI cohort,while Olaparib,Oxaliplatin,SB216763,and Axitinib had lower values.These results suggest that individuals with high CDI levels are sensitive to tyrosine kinase inhibitors and may be resistant to conventional chemotherapy.Therefore,this study constructed a gene model that can evaluate patient immunotherapy by using programmed cell death-related genes based on muti-omics.The CDI index composed of these programmed cell death-related genes reveals the heterogeneity of lung adenocarcinoma tumors and serves as a prognostic indicator for patients.展开更多
Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)...Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)remain unexplored.Methods:Initially,The Cancer Genome Atlas(TCGA)based Gene Expression Profiling Interactive Analysis(GEPIA)database (http:/gepia.cancer-pku.cn/)was used to analyze the prognostic relevance of DARS2 expression in LUAD.Further,cell counting kit(CCK)8,immunostaining,and transwell invasion assays in LUAD cell lines in vitro,as well as DARS2 silence on LUAD by tumorigenicity experiments in wivo in nude mice,were performed.Besides,we analyzed the expression levels of p-PI3K(phosphorylated Phosphotylinosital3 kinase),PI3K,AKT(Protein Kinase B),p-AKT(phosphorylated Protein Kinase B),PCNA(proliferating cell nudear antigen),cleaved-caspase 3,E cadherin,and N-cadherin proteins using the Westem blot analysis.Results:LUAD tissues showed higher DARS2 expression compared to normal tissues.Upregulation of DARS2 could be related to Tumor-Node-Metastasis(TNM)stage,high lymph node metastasis,and inferior prognosis.DARS2 silence decreased the proliferation,migration,and invasion abilities of LUAD cells.In addition,the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved:caspase 3 and E cadherin expressions in LUAD cells,coupled with the inactivation of the PI3K/AKT signaling pathway.Moreover,DARS2 silence impaired the tumonigenicity of LUAD in vivo.Interestingly,let:7b-5p could recognize DARS2 through a complementary sequence.Mechanistically,the increased let 7b 5p expression attenuated the promo oncogenic action of DARS2 during LUAD progression,which were inversely correlated to each other in the LUAD tssues Conclusion:In summary,let 7b-5p,downregulated DARS2 expression,regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.展开更多
Background:Cytotoxic T lymphocytes(CD8+T)cells function critically in mediating anti-tumor immune response in cancer patients.Characterizing the specific functions of CD8+T cells in lung adenocarcinoma(LUAD)could help ...Background:Cytotoxic T lymphocytes(CD8+T)cells function critically in mediating anti-tumor immune response in cancer patients.Characterizing the specific functions of CD8+T cells in lung adenocarcinoma(LUAD)could help better understand local anti-tumor immune responses and estimate the effect of immunotherapy.Methods:Gens related to CD8+T cells were identified by cluster analysis based on the single-cell sequencing data of three LUAD tissues and their paired normal tissues.Weighted gene co-expression network analysis(WGCNA),consensus clustering,differential expression analysis,least absolute shrinkage and selection operator(LASSO)and Cox regression analysis were conducted to classify molecular subtypes for LUAD and to develop a risk model using prognostic genes related to CD8+T cells.Expression of the genes in the prognostic model,their effects on tumor cell invasion,and interactions with CD8+T cells were verified by cell experiments.Results:This study defined two LUAD clusters(CD8+0 and CD8+1)based on CD8+T cells,with cluster CD8+0 being significantly associated with the prognosis of LUAD.Three heterogeneous subtypes(clusters 1,2,and 3)differing in prognosis,genome mutation events,and immune status were categorized using 42 prognostic genes.A prognostic model created based on 11 significant genes(including CD200R1,CLEC17A,ZC3H12D,GNG7,SNX30,CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2,and KRT81)was able to independently estimate the death risk for patients in different LUAD cohorts.Moreover,the model also showed general applicability in external validation cohorts.Low-risk patients could benefit more from taking immunotherapy and were significantly related to the resistance to anticancer drugs.The results from cell experiments demonstrated that the expression of CD200R1,CLEC17A,ZC3H12D,GNG7,and SNX30 was significantly downregulated,while that of CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2 and KRT81 was upregulated in LUAD cells.Inhibition of CD200R1 greatly increased the invasiveness of the LUAD cells,but inhibiting CDCP1 expression weakened the invasion ability of LUAD cells.Conclusion:This study defined two prognostic CD8+T cell clusters and classified three heterogeneous molecular subtypes for LUAD.A prognostic model predictive of the potential effects of immunotherapy on LUAD patients was developed.展开更多
Interferon-gamma(IFN-γ)plays a dual role in cancer;it is both a pro-and an antitumorigenic cytokine,depending on the type of cancer.The deregulation of the IFN-γcanonic pathway is associated with several disorders,i...Interferon-gamma(IFN-γ)plays a dual role in cancer;it is both a pro-and an antitumorigenic cytokine,depending on the type of cancer.The deregulation of the IFN-γcanonic pathway is associated with several disorders,including vulner-ability to viral infections,inflammation,and cancer progression.In particular,the interplay between lung adenocarcinoma(LUAD)and viral infections appears to exist in association with the deregulation of IFN-γsignaling.In this mini-review,we investigated the status of the IFN-γsignaling pathway and the expression level of its components in LUAD.Interestingly,a reduction in IFNGR1 expression seems to be associated with LUAD progression,affecting defenses against viruses such as severe acute respiratory syndrome coronavirus 2.In addition,alterations in the expression of IFNGR1 may inhibit the antiproliferative action of IFN-γsignaling in LUAD.展开更多
BACKGROUND Heat shock protein A4(HSPA4)belongs to molecular chaperone protein family which plays important roles within variable cellular activities,including cancer initiation and progression.However,the prognostic a...BACKGROUND Heat shock protein A4(HSPA4)belongs to molecular chaperone protein family which plays important roles within variable cellular activities,including cancer initiation and progression.However,the prognostic and immunological significance of HSPA4 in lung adenocarcinoma(LUAD)has not been revealed yet.AIM To explore the prognostic and immunological roles of HSPA4 to identify a novel prognostic biomarker and therapeutic target for LUAD.METHODS We assessed the prognostic and immunological significance of HSPA4 in LUAD using data from The Cancer Genome Atlas database.The association between HSPA4 expression and clinical-pathological features was assessed through Kruskal-Wallis and Wilcoxon signed-rank test.Univariate/multivariate Cox regression analyses and Kaplan-Meier curves were employed to evaluate prognostic factors,including HSPA4,in LUAD.Gene set enrichment analysis(GSEA)was conducted to identify the key signaling pathways associated with HSPA4.The correlation between HSPA4 expression and cancer immune infiltration was evaluated using single-sample gene set enrichment analysis(ssGSEA).RESULTS Overexpressing HSPA4 was significantly related to advanced pathologic TNM stage,advanced pathologic stage,progression disease status of primary therapy outcome and female subgroups with LUAD.In addition,increased HSPA4 expression was found to be related to worse disease-specific survival and overall survival.GSEA analysis indicated a significant correlation between HSPA4 and cell cycle regulation and immune response,particularly through diminishing the function of cytotoxicity cells and CD8 T cells.The ssGSEA algorithm showed a positive correlation between HSPA4 expression and infiltrating levels of Th2 cells,while a negative correlation was observed with cytotoxic cell infiltration levels.CONCLUSION Our findings indicate HSPA4 is related to prognosis and immune cell infiltrates and may act as a novel prognostic biomarker and therapeutic target for LUAD.展开更多
Background:Lung Adenocarcinoma(LUAD)is the leading cause of death from lung cancer.Cuproptosis is the latest discovered way of programmed cell death,and Cuproptosis-Related Gene(CRG)is associated with the risk of LUAD...Background:Lung Adenocarcinoma(LUAD)is the leading cause of death from lung cancer.Cuproptosis is the latest discovered way of programmed cell death,and Cuproptosis-Related Gene(CRG)is associated with the risk of LUAD.At present,there are few research of LUAD and Cuproptosis focuses on Long non-coding RNA(LncRNA).As genomics advances,LncRNA emerges as a potential target for understanding tumor progression and prognosis,offering prospects for biological targeted therapy.Therefore,this study provides new biomarkers and therapeutic targets for LUAD from the perspective of LncRNA.Methods:Gene expression,clinical outcome and gene mutation data of LUAD patients were downloaded from TCGA database.Spearman correlation was used to analyze the correlation between LncRNA and CRG.Univariate Cox,multivariate Cox and LASSO Cox regression analysis were used to construct a prognostic model of Cuproptosis-LncRNAs.GO and KEGG enrichment and immune function analysis were performed on differentially expressed genes between different risk groups.Then,immune escape analysis was performed on LUAD patients with different TIDE score.Finally,drug sensitivity analysis was performed on these differentially expressed genes.Results:A total of 2244 Cuproptosis-LncRNAs were found.Through the application of univariate Cox regression analysis,multivariate Cox regression analysis,and LASSO Cox regression analysis,a prognostic model was developed,integrating 15 Cuproptosis-LncRNAs to assess the risk of mortality.Following that,the model underwent assessment through risk score analysis,Kaplan-Meier survival analysis,risk distribution,and evaluation of survival outcomes.The results revealed an AUC value of 0.755 for the model,surpassing the AUC of other clinical pathological features.The results of KEGG analysis showed that the differentially expressed genes in different model groups were mainly involved in Amoebiasis,Fat digestion and absorption,and other signaling pathways.The results of TMB showed that the prognostic model of TMB combined with risk score could well evaluate the prognosis of patients.The TIDE scores did not exhibit a notable distinction between the two risk models.Analysis of drug sensitivity revealed that individuals in the low-risk category demonstrated greater responsiveness to 5-Fluorouracil,Axitinib,Bexarotene,and other drugs compared to those in the high-risk group.Conclusion:Our research offers a valuable reference for predicting the prognosis of LUAD,contributing to a better understanding of the future elucidation of the process and mechanism of Cuproptosis-LncRNAs in LUAD.展开更多
Objective:Lung adenocarcinoma exhibits diverse genetic and morphological backgrounds,in addition to considerable differences in clinical pathology and molecular biological characteristics.Among these,the phenomenon of...Objective:Lung adenocarcinoma exhibits diverse genetic and morphological backgrounds,in addition to considerable differences in clinical pathology and molecular biological characteristics.Among these,the phenomenon of spread through air space(STAS),a distinct mode of lung cancer infiltration,has rarely been reported.Therefore,this study aimed to explore the relationship between STAS tumor cells and the clinical and molecular characteristics of patients with lung adenocarcinoma,as well as their impact on prognosis.Methods:This study included 147 patients who were diagnosed with lung adenocarcinoma at the Inner Mongolia Autonomous Region Cancer Institute between January 2014 and December 2017.Surgical resection specimens were retrospectively analyzed.Using univariate and multivariate Cox analyses,we assessed the association between STAS and the clinicopathological features and molecular characteristics of patients with lung adenocarcinoma.Furthermore,we investigated the effects on patient prognosis.In addition,we developed a column–line plot prediction model and performed internal validation.Results:Patients with positive STAS had a significantly higher proportion of tumors with a diameter≥2 cm,with infiltration around the pleura,blood vessels,and nerves,and a pathological stage>IIB than in STAS-negative patients(P<0.05).Cox multivariate survival analysis revealed that clinical stage,STAS status,tumor size,and visceral pleural invasion were independent prognostic factors influencing the 5-year progression-free survival in patients with lung adenocarcinoma.The predictive values and P values from the Hosmer-Lemeshow test were 0.8 and 0.2,respectively,indicating no statistical difference.Receiver operating characteristic curve analysis demonstrated areas under the curve of 0.884 and 0.872 for the training and validation groups,respectively.The nomogram model exhibited the best fit with a value of 192.09.Conclusions:Clinical stage,pleural invasion,vascular invasion,peripheral nerve invasion,tumor size,and necrosis are independent prognostic factors for patients with STAS-positive lung adenocarcinoma.The nomogrambased on the clinical stage,pleural invasion,vascular invasion,peripheral nerve invasion,tumor size,and necrosis showed good accuracy,differentiation,and clinical practicality.展开更多
Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have ...Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKI–targeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence andmetastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.展开更多
The PRR11 gene(Proline Rich 11)has been implicated in lung cancer;however,relationship between PRR11 and immune infiltration is not clearly understood.In this study,we used The Cancer Genome Atlas(TCGA)data to analyze...The PRR11 gene(Proline Rich 11)has been implicated in lung cancer;however,relationship between PRR11 and immune infiltration is not clearly understood.In this study,we used The Cancer Genome Atlas(TCGA)data to analyze the lung adenocarcinoma patients;PRR11 gene expression,clinicopathological findings,enrichment,and immune infiltration were also studied.PRR11immune response expression assays in lung adenocarcinoma(LUAD)were performed using TIMER,and statistical analysis and visualization were conducted using R software.All data were verified using Gene Expression Profiling Interactive Analysis(GEPIA),and the Human Protein Atlas(HPA).We found that PRR11 was an important prognostic factor in patients with LUAD.PRR11 expression was correlated with tumor stage and progression.Gene Set Enrichment Analysis(GSEA)showed that PRR11was enriched in the cell cycle regulatory pathways.Immune infiltration analysis revealed that the number of T helper 2(Th2)cells increased when PRR11 was overexpressed.These results confirm the role of PRR11 as a prognostic marker of lung adenocarcinoma by controlling the cell cycle and influencing the immune system to facilitate lung cancer progression.展开更多
Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and C...Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90a).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiationinduced cell apoptosis.It could bind to HSP90a with a high affinity,but the affinity was drastically decreased by HSP90a Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upregulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKε/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-II/b ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90a and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.展开更多
Background:Immunotherapy has become the fastest-adopting treatment paradigm for lung cancer with improved survival.By binding with its ligand(inducible T-cell costimulator and its ligand[ICOSL]),an inducible T-cell co...Background:Immunotherapy has become the fastest-adopting treatment paradigm for lung cancer with improved survival.By binding with its ligand(inducible T-cell costimulator and its ligand[ICOSL]),an inducible T-cell co-stimulator(ICOS)could contribute to reversing immunosuppression and improving immune response and thus be a potential target for cancer immunotherapy.Methods:We selected 54 formalin-fixed,paraffin-embedded tumor tissues from cases with stage I–III lung adenocarcinoma cancer.Immunohistochemical expression of ICOS and ICOSL was evaluated.The correlation with clinical parameters in Chinese patients was also compared with TCGA results.Results:The positive rates of ICOS and ICOSL were 68%and 81.5%,respectively,in lung tumor tissues.Of these,9 cases had a low expression of ICOS,and 22 cases had a high expression of ICOS;ICOSL expression was low in 20 cases and high in 24 cases.According to the International Association for the Study of Lung Cancer(8th edition),phase I lesions were detected in 21 cases,phase II lesions in 15 cases,and phase III lesions in 18 cases.The median survival time of all patients was 44.5 months,and the median disease-free survival was 32 months.Univariate analysis showed that the factors significantly associated with overall survival were tumor size,regional lymph node involvement,stage,and expression level of ICOS/ICOSL.Survival analysis using log-rank test indicated that the lower ICOS+cell infiltration may predict poor prognosis,whereas lower ICOSL protein expression may be associated with better prognosis,but ICOSL data need further validation in larger samples due to inconsistency in TCGA mRNA prediction.Conclusion:ICOS/ICOSL might be associated with prognosis of lung cancer,and ICOS and its ligand may be potential therapeutic targets in non-small cell lung cancer.展开更多
Background:HLA-DMA presents pathogen-derived antigens to CD4+and CD8+T cells,respectively,and plays a significant part in initiating the immune response.So far,the impact of HLA expression on the prognosis of BC cells...Background:HLA-DMA presents pathogen-derived antigens to CD4+and CD8+T cells,respectively,and plays a significant part in initiating the immune response.So far,the impact of HLA expression on the prognosis of BC cells is controversial,because few studies have shown that the expressions of some HLA genes are related to the improvement of the survival rate.Up till now,however,the relationship between HLA-DMA and LUAD has not yet been assessed.Methods:We analyzed the TCGA database and assessed the prognostic value of HLA-DMA in LUAD.We conducted the Kruskal–Wallis and Wilcoxon signed-rank test and utilized logistic regression to assess the role of clinical-pathologic characteristics and HLA-DMA expression.Kaplan–Meier method and the multivariate and univariate Cox regression were also used for evaluating the prognosis-related factors of LUAD.GSEA was used to identify HLA-DMA-related key pathways.The ssGSEA of the TCGA data was used to investigate the correlations between HLA-DMA and cancer immune cell infiltration.Results:Low HLA-DMA expression was related to poorer disease-specific survival(DSS)and overall survival(OS)of LUAD patients.GSEA revealed that HLA-DMA was tightly interrelated with an immune response by the reactome activation of anterior hox genes in hindbrain development during the early embryogenesis signaling pathway.The expression of HLA-DMA was positively associated with cytotoxic cell infiltration and negatively related to the Th2 cell infiltration according to the ssGSEA.Western blotting and the CCK-8 assay showed that KD-HLA-DMA could significantly increase the proliferation of A549 cells and significantly reduce cell pyroptosis.Conclusion:All the observations implied that HLA-DMA was associated with patient prognosis and immune infiltration in LUAD.展开更多
Introduction:The difficulty in treating lung adenocarcinoma(LUAD)is caused by a shortage of knowledge about the biological mechanisms and a lack of treatment choices.Objectives:The aim of this study was to identify a ...Introduction:The difficulty in treating lung adenocarcinoma(LUAD)is caused by a shortage of knowledge about the biological mechanisms and a lack of treatment choices.Objectives:The aim of this study was to identify a valuable molecular target for the treatment of LUAD.Methods:Using multiple databases,we screened for hub genes in LUAD using Cytoscape and explored the expression and prognosis of DLG associated protein 5(DLGAP5)in LUAD.We investigated the genetic variation,functional enrichment,and epigenetic activity of DLGAP5.Furthermore,we evaluated the relationship between the tumor microenvironment(TME)and DLGAP5.Results:Our study identified 10 hub genes in LUAD:CDC45,KIAA0101,DLGAP5,CDT1,NCAPG,CCNB1,CDCA5,CDC20,KIF11,and AURKA.We discovered that DLGAP5 was overexpressed and associated with poor prognosis in LUAD.DLGAP5 exhibited an overall genetic variation frequency of 2%,and its DNA promoter was hypomethylated in LUAD(p<0.05).The expression of DLGAP5 in LUAD showed a positive correlation with the majority of N6-methyladenosine(m6A)-methylation genes.Additionally,DLGAP5 was primarily associated with the cell cycle in LUAD.Notably,there was a significant favorable association between DLGAP5 and CD274,CTLA4,HAVCR2,and LAG3 in LUAD.Conclusion:DLGAP5 may be a therapeutic target for LUAD,as it affects cancer cells proliferation and development through the regulation of cell-cycle checkpoints and modulation of immune cell infiltration and immune checkpoints in the TME.展开更多
Polo-like kinase 1(PLK1)plays a crucial role in cell mitosis and has been associated with necroptosis.However,the role of PLK1 and necroptosis in lung adenocarcinoma(LA)remains unclear.In this study,we analyzed The Ca...Polo-like kinase 1(PLK1)plays a crucial role in cell mitosis and has been associated with necroptosis.However,the role of PLK1 and necroptosis in lung adenocarcinoma(LA)remains unclear.In this study,we analyzed The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression databases to evaluate the prognostic value and mechanistic role of PLK1 in LA.PLK1 was found to be highly expressed in LA and was positively associated with advanced disease staging and poor survival outcomes.Functional enrichment analysis showed that PLK1 was involved in cell mitosis,neurotransmitter transmission,and drug metabolism.Further analysis using single-sample gene set enrichment analysis and ESTIMATE algorithm revealed a correlation between PLK1 expression and immune infiltration in LA.Silencing of PLK1 using miRNA transfection in LA cells reduced cell proliferation and increased apoptosis,as well as upregulating the expression of necroptosis-related proteins,such as RIPK1,RIPK3,and MLKL.Additionally,nude mouse transplantation tumor experiments demonstrated that silencing PLK1 reduced the growth capacity of LA cells.These findings suggest that PLK1 plays a critical role in LA progression by regulating necroptosis and immune infiltration,and may serve as a potential therapeutic target for immunotherapy.Furthermore,PLK1 expression can be used as a prognostic biomarker for LA patients.展开更多
Lung adenocarcinoma (LUAD) is the most common and deadliest subtype of lung cancer. To select moretargeted and effective treatments for individuals, further advances in classifying LUAD are urgently needed. Thenumber,...Lung adenocarcinoma (LUAD) is the most common and deadliest subtype of lung cancer. To select moretargeted and effective treatments for individuals, further advances in classifying LUAD are urgently needed. Thenumber, type, and function of T cells in the tumor microenvironment (TME) determine the progression andtreatment response of LUAD. Long noncoding RNAs (lncRNAs), may regulate T cell differentiation, development,and activation. Thus, our aim was to identify T cell-related lncRNAs (T cell-Lncs) in LUAD and to investigatewhether T cell-Lncs could serve as potential stratifiers and therapeutic targets. Seven T cell-Lncs were identified tofurther establish the T cell-related lncRNA risk score (TRS) in LUAD. Low TRS individuals were characterized byrobust immune status, fewer genomic alterations, and remarkably longer survival than high TRS individuals. Theexcellent accuracy of TRS in predicting overall survival (OS) was validated in the TCGA-LUAD training cohort andthe GEO-LUAD validation cohort. Our data demonstrated the favorable predictive power of the TRS-basednomogram, which had important clinical significance in estimating the survival probability for individuals. Inaddition, individuals with low TRS could respond better to chemotherapy and immunotherapy than those with highTRS. LINC00525 was identified as a valuable study target, and the ability of LUAD to proliferate or invade wassignificantly attenuated by downregulation of LINC00525. In conclusion, the TRS established by T cell-Lncs couldunambiguously classify LUAD patients, predict their prognosis and guide their management. Moreover, our identifiedT cell-Lncs could provide potential therapeutic targets for LUAD.展开更多
Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-rel...Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.展开更多
BACKGROUND Lung adenocarcinoma(LUAD)is the most common non-small-cell lung cancer,with a high incidence and a poor prognosis.AIM To construct effective predictive models to evaluate the prognosis of LUAD patients.METH...BACKGROUND Lung adenocarcinoma(LUAD)is the most common non-small-cell lung cancer,with a high incidence and a poor prognosis.AIM To construct effective predictive models to evaluate the prognosis of LUAD patients.METHODS In this study,we thoroughly mined LUAD genomic data from the Gene Expression Omnibus(GEO)(GSE43458,GSE32863,and GSE27262)and the Cancer Genome Atlas(TCGA)datasets,including 698 LUAD and 172 healthy(or adjacent normal)lung tissue samples.Univariate regression and LASSO regression analyses were used to screen differentially expressed genes(DEGs)related to patient prognosis,and multivariate Cox regression analysis was applied to establish the risk score equation and construct the survival prognosis model.Receiver operating characteristic curve and Kaplan-Meier survival analyses with clinically independent prognostic parameters were performed to verify the predictive power of the model and further establish a prognostic nomogram.RESULTS A total of 380 DEGs were identified in LUAD tissues through GEO and TCGA datasets,and 5 DEGs(TCN1,CENPF,MAOB,CRTAC1 and PLEK2)were screened out by multivariate Cox regression analysis,indicating that the prognostic risk model could be used as an independent prognostic factor(Hazard ratio=1.520,P<0.001).Internal and external validation of the model confirmed that the prediction model had good sensitivity and specificity(Area under the curve=0.754,0.737).Combining genetic models and clinical prognostic factors,nomograms can also predict overall survival more effectively.CONCLUSION A 5-mRNA-based model was constructed to predict the prognosis of lung adenocarcinoma,which may provide clinicians with reliable prognostic assessment tools and help clinical treatment decisions.展开更多
Objective:To investigate the effects of Eriocitrin on the proliferation and migration of Lung adenocarcinoma(LUAD)cells A549 and H1299,and the mechanism of Epithelial-Mesenchymal Transition(EMT).Methods:The effects of...Objective:To investigate the effects of Eriocitrin on the proliferation and migration of Lung adenocarcinoma(LUAD)cells A549 and H1299,and the mechanism of Epithelial-Mesenchymal Transition(EMT).Methods:The effects of different Eriocitrin on the proliferation of LUAD cells A549 and H1299 were examined by CCK8 method.EMT-associated epithelial calmodulin(E-cadherin and N-cadherin),vimentin,ferroptosis-associated protein SLC7A11,GPX4,FTH were detected by Western Blot and expression of mRNA of EMT marker molecules E-cadherin,N-cadherin,Snail were detected by qRT-PCR.Effects of saccharomyces cerevisiae suberin on ferroptosis in LUAD cells as observed by lipid reactive oxygen species(ROS)assay.Results:Eriocitrin could significantly inhibit the proliferative behavior of LUAD cells A549 and H1299 and showed a certain dose-and time-dependence.Compared with the control group,different concentrations of Eriocitrin could significantly reduce the scratch healing rate after 24 and 48 h of action,and the difference was statistically significant(P<0.01).The expression of ROS is increased,EMT-related protein E-cadherin was increased in LUAD cells A549 and H1299 compared with the control group after the intervention with Eriocitrin.N-cadherin and Vimentin expression was decreased.E-cadherin mRNA expression was increased,and N-cadherin,Snail mRNA expression was decreased,expression of ferroptosis-associated protein SLC7A11,GPX4,FTH was decreased,the difference was statistically significant(P<0.05).Conclusion:Eriocitrin may inhibit the proliferation and migration of LUAD cells by regulating the EMT pathway and has potential application in LUAD prevention and adjuvant chemotherapy.展开更多
Objective:To investigate the expression level,clinical prognosis,genetic changes,methylation value,biological function and immunomodulatory effects of PHF19 in lung adenocarcinoma.Methods:Based on the RNA cohort data ...Objective:To investigate the expression level,clinical prognosis,genetic changes,methylation value,biological function and immunomodulatory effects of PHF19 in lung adenocarcinoma.Methods:Based on the RNA cohort data of lung adenocarcinoma in the Cancer Genome Atlas(TCGA)database,the expression difference of PHF19 between lung adenocarcinoma and normal tissues and the relationship between the expression level and the prognosis of patients were analyzed by using TIMER database and UALCAN database.The gene mutation of PHF19 in lung adenocarcinoma was analyzed in cBioPortal database and TIMER database.The promoter methylation level of PHF19 in lung adenocarcinoma was analyzed in UALCAN database.The enrichment of PHF19 co-expression gene was analyzed in LinkedOmics database and KEGG database.The correlation between the expression of PHF19 in lung adenocarcinoma and the level of immunoinfiltration was explored in the TIMER database.Results:The expression of PHF19 in lung adenocarcinoma tissues was up-regulated,and its high expression was significantly correlated with the pathological stage,lymph node metastasis and shortened overall survival of lung adenocarcinoma patients.Genetic variation was found in 0.9%of patients,amplification and missense mutation were the most common mutations,and TP53 mutation could lead to the high expression of PHF19.The promoter methylation level of PHF19 significantly decreased in lung adenocarcinoma.The function of PHF19 was focused on the process of cell mitosis and cell cycle.The expression level of PHF19 was significantly correlated with tumor immune cell infiltration and immune checkpoint expression.Conclusion:PHF19 can be used as a marker of poor prognosis of lung adenocarcinoma and plays an important role in the occurrence and development of lung adenocarcinoma.展开更多
基金supported by the National Natural Science Foundation of China(No.81703001)the Natural Science Foundation of Hebei Province(No.H2021406021),Hebei Province Medical Science Research Project(Nos.20210247,20221335)Hebei Province Government-Funded Clinical Medical Outstanding Talents Project,Chengde Medical University Scientific Research Major Projects(No.KY2020005).
文摘The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the clinic.It has been shown that microRNAs(miRNAs)play a significant role in tumor chemoresistance.In this study,miR-125b was identified as a specific cisplatin(DDP)-resistant gene in LUAD,as indicated by the bioinformatics analysis and the real-time quantitative PCR assay.The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time.MiR-125b decreased the A549/DDP proliferation,and the multiple drug resistance-and autophagy-related protein expression levels,which were all reversed by the inhibition of miR-125b.In addition,xenografts of human tumors in nude mice were suppressed by miR-125b,demonstrating that through autophagy regulation,miR-125b could reverse the DDP resistance in LUAD cells,both in vitro and in vivo.Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L,which in turn inhibited autophagy and reversed chemoresistance.Based on these findings,miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.
基金National Natural Science Foundation of China(Grant No.81273297)Shenyang Science and Technology Plan.Public Health R&D Special Project(21-173-9-67).
文摘Advanced LUAD shows limited response to treatment including immune therapy.With the development of sequencing omics,it is urgent to combine high-throughput multi-omics data to identify new immune checkpoint therapeutic response markers.Using GSE72094(n=386)and GSE31210(n=226)gene expression profile data in the GEO database,we identified genes associated with lung adenocarcinoma(LUAD)death using tools such as“edgeR”and“maftools”and visualized the characteristics of these genes using the“circlize”R package.We constructed a prognostic model based on death-related genes and optimized the model using LASSO-Cox regression methods.By calculating the cell death index(CDI)of each individual,we divided LUAD patients into high and low CDI groups and examined the relationship between CDI and overall survival time by principal component analysis(PCA)and Kaplan-Meier analysis.We also used the“ConsensusClusterPlus”tool for unsupervised clustering of LUAD subtypes based on model genes.In addition,we collected data on the expression of immunomodulatory genes and model genes for each cohort and performed tumor microenvironment analyses.We also used the TIDE algorithm to predict immunotherapy responses in the CDI cohort.Finally,we studied the effect of PRKCD on the proliferation and migration of LUAD cells through cell culture experiments.The study utilized the TCGA-LUAD cohort(n=493)and identified 2,901 genes that are differentially expressed in patients with LUAD.Through KEGG and GO enrichment analysis,these genes were found to be involved in a wide range of biological pathways.The study also used univariate Cox regression models and LASSO regression analyses to identify 17 candidate genes that were best associated with mortality prognostic risk scores.By comparing the overall survival(OS)outcomes of patients with different CDI values,it was found that increased CDI levels were significantly associated with lower OS rates.In addition,the study used unsupervised cluster analysis to divide 115 LUAD patients into two distinct clusters with significant differences in OS timing.Finally,a prognostic indicator called CDI was established and its feasibility as an independent prognostic indicator was evaluated by Cox proportional risk regression analysis.The immunotherapy efficacy was more sensitive in the group with high expression of programmed cell death models.Relationship between programmed cell death(PCD)signature models and drug reactivity.After evaluating the median inhibitory concentration(IC50)of various drugs in LUAD samples,statistically significant differences in IC50 values were found in cohorts with high and low CDI status.Specifically,Gefitinib and Lapatinib had higher IC50 values in the high-CDI cohort,while Olaparib,Oxaliplatin,SB216763,and Axitinib had lower values.These results suggest that individuals with high CDI levels are sensitive to tyrosine kinase inhibitors and may be resistant to conventional chemotherapy.Therefore,this study constructed a gene model that can evaluate patient immunotherapy by using programmed cell death-related genes based on muti-omics.The CDI index composed of these programmed cell death-related genes reveals the heterogeneity of lung adenocarcinoma tumors and serves as a prognostic indicator for patients.
文摘Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)remain unexplored.Methods:Initially,The Cancer Genome Atlas(TCGA)based Gene Expression Profiling Interactive Analysis(GEPIA)database (http:/gepia.cancer-pku.cn/)was used to analyze the prognostic relevance of DARS2 expression in LUAD.Further,cell counting kit(CCK)8,immunostaining,and transwell invasion assays in LUAD cell lines in vitro,as well as DARS2 silence on LUAD by tumorigenicity experiments in wivo in nude mice,were performed.Besides,we analyzed the expression levels of p-PI3K(phosphorylated Phosphotylinosital3 kinase),PI3K,AKT(Protein Kinase B),p-AKT(phosphorylated Protein Kinase B),PCNA(proliferating cell nudear antigen),cleaved-caspase 3,E cadherin,and N-cadherin proteins using the Westem blot analysis.Results:LUAD tissues showed higher DARS2 expression compared to normal tissues.Upregulation of DARS2 could be related to Tumor-Node-Metastasis(TNM)stage,high lymph node metastasis,and inferior prognosis.DARS2 silence decreased the proliferation,migration,and invasion abilities of LUAD cells.In addition,the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved:caspase 3 and E cadherin expressions in LUAD cells,coupled with the inactivation of the PI3K/AKT signaling pathway.Moreover,DARS2 silence impaired the tumonigenicity of LUAD in vivo.Interestingly,let:7b-5p could recognize DARS2 through a complementary sequence.Mechanistically,the increased let 7b 5p expression attenuated the promo oncogenic action of DARS2 during LUAD progression,which were inversely correlated to each other in the LUAD tssues Conclusion:In summary,let 7b-5p,downregulated DARS2 expression,regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.
文摘Background:Cytotoxic T lymphocytes(CD8+T)cells function critically in mediating anti-tumor immune response in cancer patients.Characterizing the specific functions of CD8+T cells in lung adenocarcinoma(LUAD)could help better understand local anti-tumor immune responses and estimate the effect of immunotherapy.Methods:Gens related to CD8+T cells were identified by cluster analysis based on the single-cell sequencing data of three LUAD tissues and their paired normal tissues.Weighted gene co-expression network analysis(WGCNA),consensus clustering,differential expression analysis,least absolute shrinkage and selection operator(LASSO)and Cox regression analysis were conducted to classify molecular subtypes for LUAD and to develop a risk model using prognostic genes related to CD8+T cells.Expression of the genes in the prognostic model,their effects on tumor cell invasion,and interactions with CD8+T cells were verified by cell experiments.Results:This study defined two LUAD clusters(CD8+0 and CD8+1)based on CD8+T cells,with cluster CD8+0 being significantly associated with the prognosis of LUAD.Three heterogeneous subtypes(clusters 1,2,and 3)differing in prognosis,genome mutation events,and immune status were categorized using 42 prognostic genes.A prognostic model created based on 11 significant genes(including CD200R1,CLEC17A,ZC3H12D,GNG7,SNX30,CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2,and KRT81)was able to independently estimate the death risk for patients in different LUAD cohorts.Moreover,the model also showed general applicability in external validation cohorts.Low-risk patients could benefit more from taking immunotherapy and were significantly related to the resistance to anticancer drugs.The results from cell experiments demonstrated that the expression of CD200R1,CLEC17A,ZC3H12D,GNG7,and SNX30 was significantly downregulated,while that of CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2 and KRT81 was upregulated in LUAD cells.Inhibition of CD200R1 greatly increased the invasiveness of the LUAD cells,but inhibiting CDCP1 expression weakened the invasion ability of LUAD cells.Conclusion:This study defined two prognostic CD8+T cell clusters and classified three heterogeneous molecular subtypes for LUAD.A prognostic model predictive of the potential effects of immunotherapy on LUAD patients was developed.
文摘Interferon-gamma(IFN-γ)plays a dual role in cancer;it is both a pro-and an antitumorigenic cytokine,depending on the type of cancer.The deregulation of the IFN-γcanonic pathway is associated with several disorders,including vulner-ability to viral infections,inflammation,and cancer progression.In particular,the interplay between lung adenocarcinoma(LUAD)and viral infections appears to exist in association with the deregulation of IFN-γsignaling.In this mini-review,we investigated the status of the IFN-γsignaling pathway and the expression level of its components in LUAD.Interestingly,a reduction in IFNGR1 expression seems to be associated with LUAD progression,affecting defenses against viruses such as severe acute respiratory syndrome coronavirus 2.In addition,alterations in the expression of IFNGR1 may inhibit the antiproliferative action of IFN-γsignaling in LUAD.
文摘BACKGROUND Heat shock protein A4(HSPA4)belongs to molecular chaperone protein family which plays important roles within variable cellular activities,including cancer initiation and progression.However,the prognostic and immunological significance of HSPA4 in lung adenocarcinoma(LUAD)has not been revealed yet.AIM To explore the prognostic and immunological roles of HSPA4 to identify a novel prognostic biomarker and therapeutic target for LUAD.METHODS We assessed the prognostic and immunological significance of HSPA4 in LUAD using data from The Cancer Genome Atlas database.The association between HSPA4 expression and clinical-pathological features was assessed through Kruskal-Wallis and Wilcoxon signed-rank test.Univariate/multivariate Cox regression analyses and Kaplan-Meier curves were employed to evaluate prognostic factors,including HSPA4,in LUAD.Gene set enrichment analysis(GSEA)was conducted to identify the key signaling pathways associated with HSPA4.The correlation between HSPA4 expression and cancer immune infiltration was evaluated using single-sample gene set enrichment analysis(ssGSEA).RESULTS Overexpressing HSPA4 was significantly related to advanced pathologic TNM stage,advanced pathologic stage,progression disease status of primary therapy outcome and female subgroups with LUAD.In addition,increased HSPA4 expression was found to be related to worse disease-specific survival and overall survival.GSEA analysis indicated a significant correlation between HSPA4 and cell cycle regulation and immune response,particularly through diminishing the function of cytotoxicity cells and CD8 T cells.The ssGSEA algorithm showed a positive correlation between HSPA4 expression and infiltrating levels of Th2 cells,while a negative correlation was observed with cytotoxic cell infiltration levels.CONCLUSION Our findings indicate HSPA4 is related to prognosis and immune cell infiltrates and may act as a novel prognostic biomarker and therapeutic target for LUAD.
文摘Background:Lung Adenocarcinoma(LUAD)is the leading cause of death from lung cancer.Cuproptosis is the latest discovered way of programmed cell death,and Cuproptosis-Related Gene(CRG)is associated with the risk of LUAD.At present,there are few research of LUAD and Cuproptosis focuses on Long non-coding RNA(LncRNA).As genomics advances,LncRNA emerges as a potential target for understanding tumor progression and prognosis,offering prospects for biological targeted therapy.Therefore,this study provides new biomarkers and therapeutic targets for LUAD from the perspective of LncRNA.Methods:Gene expression,clinical outcome and gene mutation data of LUAD patients were downloaded from TCGA database.Spearman correlation was used to analyze the correlation between LncRNA and CRG.Univariate Cox,multivariate Cox and LASSO Cox regression analysis were used to construct a prognostic model of Cuproptosis-LncRNAs.GO and KEGG enrichment and immune function analysis were performed on differentially expressed genes between different risk groups.Then,immune escape analysis was performed on LUAD patients with different TIDE score.Finally,drug sensitivity analysis was performed on these differentially expressed genes.Results:A total of 2244 Cuproptosis-LncRNAs were found.Through the application of univariate Cox regression analysis,multivariate Cox regression analysis,and LASSO Cox regression analysis,a prognostic model was developed,integrating 15 Cuproptosis-LncRNAs to assess the risk of mortality.Following that,the model underwent assessment through risk score analysis,Kaplan-Meier survival analysis,risk distribution,and evaluation of survival outcomes.The results revealed an AUC value of 0.755 for the model,surpassing the AUC of other clinical pathological features.The results of KEGG analysis showed that the differentially expressed genes in different model groups were mainly involved in Amoebiasis,Fat digestion and absorption,and other signaling pathways.The results of TMB showed that the prognostic model of TMB combined with risk score could well evaluate the prognosis of patients.The TIDE scores did not exhibit a notable distinction between the two risk models.Analysis of drug sensitivity revealed that individuals in the low-risk category demonstrated greater responsiveness to 5-Fluorouracil,Axitinib,Bexarotene,and other drugs compared to those in the high-risk group.Conclusion:Our research offers a valuable reference for predicting the prognosis of LUAD,contributing to a better understanding of the future elucidation of the process and mechanism of Cuproptosis-LncRNAs in LUAD.
基金Funded by the Health Science and Technology Program of Inner Mongolia Autonomous Region(no.202201061)Supported by the Joint Project of theMillion Science and Technology Initiatives of Inner Mongolia Medical University(no.YKD2020KJBW(LH)057).
文摘Objective:Lung adenocarcinoma exhibits diverse genetic and morphological backgrounds,in addition to considerable differences in clinical pathology and molecular biological characteristics.Among these,the phenomenon of spread through air space(STAS),a distinct mode of lung cancer infiltration,has rarely been reported.Therefore,this study aimed to explore the relationship between STAS tumor cells and the clinical and molecular characteristics of patients with lung adenocarcinoma,as well as their impact on prognosis.Methods:This study included 147 patients who were diagnosed with lung adenocarcinoma at the Inner Mongolia Autonomous Region Cancer Institute between January 2014 and December 2017.Surgical resection specimens were retrospectively analyzed.Using univariate and multivariate Cox analyses,we assessed the association between STAS and the clinicopathological features and molecular characteristics of patients with lung adenocarcinoma.Furthermore,we investigated the effects on patient prognosis.In addition,we developed a column–line plot prediction model and performed internal validation.Results:Patients with positive STAS had a significantly higher proportion of tumors with a diameter≥2 cm,with infiltration around the pleura,blood vessels,and nerves,and a pathological stage>IIB than in STAS-negative patients(P<0.05).Cox multivariate survival analysis revealed that clinical stage,STAS status,tumor size,and visceral pleural invasion were independent prognostic factors influencing the 5-year progression-free survival in patients with lung adenocarcinoma.The predictive values and P values from the Hosmer-Lemeshow test were 0.8 and 0.2,respectively,indicating no statistical difference.Receiver operating characteristic curve analysis demonstrated areas under the curve of 0.884 and 0.872 for the training and validation groups,respectively.The nomogram model exhibited the best fit with a value of 192.09.Conclusions:Clinical stage,pleural invasion,vascular invasion,peripheral nerve invasion,tumor size,and necrosis are independent prognostic factors for patients with STAS-positive lung adenocarcinoma.The nomogrambased on the clinical stage,pleural invasion,vascular invasion,peripheral nerve invasion,tumor size,and necrosis showed good accuracy,differentiation,and clinical practicality.
基金supported by the Natural Science Foundation of Hubei Province(no.2021CFB372 to Hua Xiong).
文摘Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKI–targeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence andmetastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.
基金supported by the Traditional Chinese Medicine Science and Technology Project of Shandong Province [grant number 2020Q139]。
文摘The PRR11 gene(Proline Rich 11)has been implicated in lung cancer;however,relationship between PRR11 and immune infiltration is not clearly understood.In this study,we used The Cancer Genome Atlas(TCGA)data to analyze the lung adenocarcinoma patients;PRR11 gene expression,clinicopathological findings,enrichment,and immune infiltration were also studied.PRR11immune response expression assays in lung adenocarcinoma(LUAD)were performed using TIMER,and statistical analysis and visualization were conducted using R software.All data were verified using Gene Expression Profiling Interactive Analysis(GEPIA),and the Human Protein Atlas(HPA).We found that PRR11 was an important prognostic factor in patients with LUAD.PRR11 expression was correlated with tumor stage and progression.Gene Set Enrichment Analysis(GSEA)showed that PRR11was enriched in the cell cycle regulatory pathways.Immune infiltration analysis revealed that the number of T helper 2(Th2)cells increased when PRR11 was overexpressed.These results confirm the role of PRR11 as a prognostic marker of lung adenocarcinoma by controlling the cell cycle and influencing the immune system to facilitate lung cancer progression.
基金supported by grants from the Project of Sichuan Science and Technology Department,China(Grant No.:2021YJ0010).
文摘Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90a).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiationinduced cell apoptosis.It could bind to HSP90a with a high affinity,but the affinity was drastically decreased by HSP90a Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upregulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKε/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-II/b ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90a and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.
基金the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS,nos:2022-I2M-JB-011,2022-I2M-1-014)the National Natural Science Foundation of China(82293684)the National Key R&D Program of China(2022YFA0806400).
文摘Background:Immunotherapy has become the fastest-adopting treatment paradigm for lung cancer with improved survival.By binding with its ligand(inducible T-cell costimulator and its ligand[ICOSL]),an inducible T-cell co-stimulator(ICOS)could contribute to reversing immunosuppression and improving immune response and thus be a potential target for cancer immunotherapy.Methods:We selected 54 formalin-fixed,paraffin-embedded tumor tissues from cases with stage I–III lung adenocarcinoma cancer.Immunohistochemical expression of ICOS and ICOSL was evaluated.The correlation with clinical parameters in Chinese patients was also compared with TCGA results.Results:The positive rates of ICOS and ICOSL were 68%and 81.5%,respectively,in lung tumor tissues.Of these,9 cases had a low expression of ICOS,and 22 cases had a high expression of ICOS;ICOSL expression was low in 20 cases and high in 24 cases.According to the International Association for the Study of Lung Cancer(8th edition),phase I lesions were detected in 21 cases,phase II lesions in 15 cases,and phase III lesions in 18 cases.The median survival time of all patients was 44.5 months,and the median disease-free survival was 32 months.Univariate analysis showed that the factors significantly associated with overall survival were tumor size,regional lymph node involvement,stage,and expression level of ICOS/ICOSL.Survival analysis using log-rank test indicated that the lower ICOS+cell infiltration may predict poor prognosis,whereas lower ICOSL protein expression may be associated with better prognosis,but ICOSL data need further validation in larger samples due to inconsistency in TCGA mRNA prediction.Conclusion:ICOS/ICOSL might be associated with prognosis of lung cancer,and ICOS and its ligand may be potential therapeutic targets in non-small cell lung cancer.
基金the National Natural Science Foundation of China(Grant No.81971036)China Medical and Health Development Foundation(Grant Nos.C202212-006,C202212-0014).
文摘Background:HLA-DMA presents pathogen-derived antigens to CD4+and CD8+T cells,respectively,and plays a significant part in initiating the immune response.So far,the impact of HLA expression on the prognosis of BC cells is controversial,because few studies have shown that the expressions of some HLA genes are related to the improvement of the survival rate.Up till now,however,the relationship between HLA-DMA and LUAD has not yet been assessed.Methods:We analyzed the TCGA database and assessed the prognostic value of HLA-DMA in LUAD.We conducted the Kruskal–Wallis and Wilcoxon signed-rank test and utilized logistic regression to assess the role of clinical-pathologic characteristics and HLA-DMA expression.Kaplan–Meier method and the multivariate and univariate Cox regression were also used for evaluating the prognosis-related factors of LUAD.GSEA was used to identify HLA-DMA-related key pathways.The ssGSEA of the TCGA data was used to investigate the correlations between HLA-DMA and cancer immune cell infiltration.Results:Low HLA-DMA expression was related to poorer disease-specific survival(DSS)and overall survival(OS)of LUAD patients.GSEA revealed that HLA-DMA was tightly interrelated with an immune response by the reactome activation of anterior hox genes in hindbrain development during the early embryogenesis signaling pathway.The expression of HLA-DMA was positively associated with cytotoxic cell infiltration and negatively related to the Th2 cell infiltration according to the ssGSEA.Western blotting and the CCK-8 assay showed that KD-HLA-DMA could significantly increase the proliferation of A549 cells and significantly reduce cell pyroptosis.Conclusion:All the observations implied that HLA-DMA was associated with patient prognosis and immune infiltration in LUAD.
基金funded by the supporting funds for scientific research of the Sixth Affiliated Hospital,Sun Yat-sen University(P20200217202404781).
文摘Introduction:The difficulty in treating lung adenocarcinoma(LUAD)is caused by a shortage of knowledge about the biological mechanisms and a lack of treatment choices.Objectives:The aim of this study was to identify a valuable molecular target for the treatment of LUAD.Methods:Using multiple databases,we screened for hub genes in LUAD using Cytoscape and explored the expression and prognosis of DLG associated protein 5(DLGAP5)in LUAD.We investigated the genetic variation,functional enrichment,and epigenetic activity of DLGAP5.Furthermore,we evaluated the relationship between the tumor microenvironment(TME)and DLGAP5.Results:Our study identified 10 hub genes in LUAD:CDC45,KIAA0101,DLGAP5,CDT1,NCAPG,CCNB1,CDCA5,CDC20,KIF11,and AURKA.We discovered that DLGAP5 was overexpressed and associated with poor prognosis in LUAD.DLGAP5 exhibited an overall genetic variation frequency of 2%,and its DNA promoter was hypomethylated in LUAD(p<0.05).The expression of DLGAP5 in LUAD showed a positive correlation with the majority of N6-methyladenosine(m6A)-methylation genes.Additionally,DLGAP5 was primarily associated with the cell cycle in LUAD.Notably,there was a significant favorable association between DLGAP5 and CD274,CTLA4,HAVCR2,and LAG3 in LUAD.Conclusion:DLGAP5 may be a therapeutic target for LUAD,as it affects cancer cells proliferation and development through the regulation of cell-cycle checkpoints and modulation of immune cell infiltration and immune checkpoints in the TME.
基金supported by the Natural Science Research Project of Colleges and Universities in Anhui Province(KJ2021A0557)the grants from the Opening Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University(Chinese Traditional Medicine)(ZYXZD2019004)+2 种基金Zhejiang Chinese Medical Universitythe National Natural Science Foundation of China(ZYXZD81973643)Zhejiang Chinese Medicine Science and Technology Project(No.2023ZL467).
文摘Polo-like kinase 1(PLK1)plays a crucial role in cell mitosis and has been associated with necroptosis.However,the role of PLK1 and necroptosis in lung adenocarcinoma(LA)remains unclear.In this study,we analyzed The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression databases to evaluate the prognostic value and mechanistic role of PLK1 in LA.PLK1 was found to be highly expressed in LA and was positively associated with advanced disease staging and poor survival outcomes.Functional enrichment analysis showed that PLK1 was involved in cell mitosis,neurotransmitter transmission,and drug metabolism.Further analysis using single-sample gene set enrichment analysis and ESTIMATE algorithm revealed a correlation between PLK1 expression and immune infiltration in LA.Silencing of PLK1 using miRNA transfection in LA cells reduced cell proliferation and increased apoptosis,as well as upregulating the expression of necroptosis-related proteins,such as RIPK1,RIPK3,and MLKL.Additionally,nude mouse transplantation tumor experiments demonstrated that silencing PLK1 reduced the growth capacity of LA cells.These findings suggest that PLK1 plays a critical role in LA progression by regulating necroptosis and immune infiltration,and may serve as a potential therapeutic target for immunotherapy.Furthermore,PLK1 expression can be used as a prognostic biomarker for LA patients.
基金supported by the following funds:the Key Research and Development Project of the Science and Technology Department of Sichuan Province(Grant Nos.2021YFS0202 and 2021YFS0229)the Natural Science Foundation of Sichuan Province(Grant No.2022NSFSC1326)+1 种基金Postdoctoral Research Fund of West China Hospital(Grant Nos.2019HXBH056 and 2020HXBH066)China Postdoctoral Science Foundation(Grant No.2022T150454).
文摘Lung adenocarcinoma (LUAD) is the most common and deadliest subtype of lung cancer. To select moretargeted and effective treatments for individuals, further advances in classifying LUAD are urgently needed. Thenumber, type, and function of T cells in the tumor microenvironment (TME) determine the progression andtreatment response of LUAD. Long noncoding RNAs (lncRNAs), may regulate T cell differentiation, development,and activation. Thus, our aim was to identify T cell-related lncRNAs (T cell-Lncs) in LUAD and to investigatewhether T cell-Lncs could serve as potential stratifiers and therapeutic targets. Seven T cell-Lncs were identified tofurther establish the T cell-related lncRNA risk score (TRS) in LUAD. Low TRS individuals were characterized byrobust immune status, fewer genomic alterations, and remarkably longer survival than high TRS individuals. Theexcellent accuracy of TRS in predicting overall survival (OS) was validated in the TCGA-LUAD training cohort andthe GEO-LUAD validation cohort. Our data demonstrated the favorable predictive power of the TRS-basednomogram, which had important clinical significance in estimating the survival probability for individuals. Inaddition, individuals with low TRS could respond better to chemotherapy and immunotherapy than those with highTRS. LINC00525 was identified as a valuable study target, and the ability of LUAD to proliferate or invade wassignificantly attenuated by downregulation of LINC00525. In conclusion, the TRS established by T cell-Lncs couldunambiguously classify LUAD patients, predict their prognosis and guide their management. Moreover, our identifiedT cell-Lncs could provide potential therapeutic targets for LUAD.
文摘Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.
基金the Science and Technology Development Fund of the Pudong New Area,No.PKJ2021-Y53the National Natural Science Foundation of China,No.81974315.
文摘BACKGROUND Lung adenocarcinoma(LUAD)is the most common non-small-cell lung cancer,with a high incidence and a poor prognosis.AIM To construct effective predictive models to evaluate the prognosis of LUAD patients.METHODS In this study,we thoroughly mined LUAD genomic data from the Gene Expression Omnibus(GEO)(GSE43458,GSE32863,and GSE27262)and the Cancer Genome Atlas(TCGA)datasets,including 698 LUAD and 172 healthy(or adjacent normal)lung tissue samples.Univariate regression and LASSO regression analyses were used to screen differentially expressed genes(DEGs)related to patient prognosis,and multivariate Cox regression analysis was applied to establish the risk score equation and construct the survival prognosis model.Receiver operating characteristic curve and Kaplan-Meier survival analyses with clinically independent prognostic parameters were performed to verify the predictive power of the model and further establish a prognostic nomogram.RESULTS A total of 380 DEGs were identified in LUAD tissues through GEO and TCGA datasets,and 5 DEGs(TCN1,CENPF,MAOB,CRTAC1 and PLEK2)were screened out by multivariate Cox regression analysis,indicating that the prognostic risk model could be used as an independent prognostic factor(Hazard ratio=1.520,P<0.001).Internal and external validation of the model confirmed that the prediction model had good sensitivity and specificity(Area under the curve=0.754,0.737).Combining genetic models and clinical prognostic factors,nomograms can also predict overall survival more effectively.CONCLUSION A 5-mRNA-based model was constructed to predict the prognosis of lung adenocarcinoma,which may provide clinicians with reliable prognostic assessment tools and help clinical treatment decisions.
基金Basic Research Foundation for Universities of the CPC Central Committee(No.2042021KF0081)Innovation Group of Natural Science Foundation of Hubei Province(2020CFA027)。
文摘Objective:To investigate the effects of Eriocitrin on the proliferation and migration of Lung adenocarcinoma(LUAD)cells A549 and H1299,and the mechanism of Epithelial-Mesenchymal Transition(EMT).Methods:The effects of different Eriocitrin on the proliferation of LUAD cells A549 and H1299 were examined by CCK8 method.EMT-associated epithelial calmodulin(E-cadherin and N-cadherin),vimentin,ferroptosis-associated protein SLC7A11,GPX4,FTH were detected by Western Blot and expression of mRNA of EMT marker molecules E-cadherin,N-cadherin,Snail were detected by qRT-PCR.Effects of saccharomyces cerevisiae suberin on ferroptosis in LUAD cells as observed by lipid reactive oxygen species(ROS)assay.Results:Eriocitrin could significantly inhibit the proliferative behavior of LUAD cells A549 and H1299 and showed a certain dose-and time-dependence.Compared with the control group,different concentrations of Eriocitrin could significantly reduce the scratch healing rate after 24 and 48 h of action,and the difference was statistically significant(P<0.01).The expression of ROS is increased,EMT-related protein E-cadherin was increased in LUAD cells A549 and H1299 compared with the control group after the intervention with Eriocitrin.N-cadherin and Vimentin expression was decreased.E-cadherin mRNA expression was increased,and N-cadherin,Snail mRNA expression was decreased,expression of ferroptosis-associated protein SLC7A11,GPX4,FTH was decreased,the difference was statistically significant(P<0.05).Conclusion:Eriocitrin may inhibit the proliferation and migration of LUAD cells by regulating the EMT pathway and has potential application in LUAD prevention and adjuvant chemotherapy.
基金Natural Science Foundation of Shanxi Province(201901D111391)。
文摘Objective:To investigate the expression level,clinical prognosis,genetic changes,methylation value,biological function and immunomodulatory effects of PHF19 in lung adenocarcinoma.Methods:Based on the RNA cohort data of lung adenocarcinoma in the Cancer Genome Atlas(TCGA)database,the expression difference of PHF19 between lung adenocarcinoma and normal tissues and the relationship between the expression level and the prognosis of patients were analyzed by using TIMER database and UALCAN database.The gene mutation of PHF19 in lung adenocarcinoma was analyzed in cBioPortal database and TIMER database.The promoter methylation level of PHF19 in lung adenocarcinoma was analyzed in UALCAN database.The enrichment of PHF19 co-expression gene was analyzed in LinkedOmics database and KEGG database.The correlation between the expression of PHF19 in lung adenocarcinoma and the level of immunoinfiltration was explored in the TIMER database.Results:The expression of PHF19 in lung adenocarcinoma tissues was up-regulated,and its high expression was significantly correlated with the pathological stage,lymph node metastasis and shortened overall survival of lung adenocarcinoma patients.Genetic variation was found in 0.9%of patients,amplification and missense mutation were the most common mutations,and TP53 mutation could lead to the high expression of PHF19.The promoter methylation level of PHF19 significantly decreased in lung adenocarcinoma.The function of PHF19 was focused on the process of cell mitosis and cell cycle.The expression level of PHF19 was significantly correlated with tumor immune cell infiltration and immune checkpoint expression.Conclusion:PHF19 can be used as a marker of poor prognosis of lung adenocarcinoma and plays an important role in the occurrence and development of lung adenocarcinoma.
