Prognosis Of Lung Adenocarcinoma Patients Research Articles

SERPINE2/PN-1 regulates the DNA damage response and radioresistance by activating ATM in lung cancer.

Although the DNA damage response (DDR) is associated with the radioresistance characteristics of lung cancer cells, the specific regulators and underlying mechanisms of the DDR are unclear. Here, we identified the serine proteinase inhibitor clade E member 2 (SERPINE2) as a modulator of radiosensitivity and the DDR in lung cancer. Cells exhibiting radioresistance after ionizing radiation show upregulation of SERPINE2, and SERPINE2 knockdown improves tumor radiosensitivity in vitro and in vivo. Functionally, SERPINE2 deficiency causes a reduction in homologous recombination repair, rapid recovery of cell cycle checkpoints, and suppression of migration and invasion. Mechanistically, SERPINE2 knockdown inhibits the accumulation of p-ATM and the downstream repair protein RAD51 during DNA repair, and RAD51 can restore DNA damage and radioresistance phenotypes in lung cancer cells. Furthermore, SERPINE2 can directly interact with MRE11 and ATM to facilitate its phosphorylation in HR-mediated DSB repair. In addition, high SERPINE2 expression correlates with dismal prognosis in lung adenocarcinoma patients, and a high serum SERPINE2 concentration predicts a poor response to radiotherapy in non-small cell lung cancer patients. In summary, these findings indicate a novel regulatory mechanism by which SERPINE2 modulates the DDR and radioresistance in lung cancer.

A novel epithelial-mesenchymal transition-related gene signature for prognosis prediction in patients with lung adenocarcinoma

Traditional pathological diagnoses and clinical methods are insufficient to accurately predict the prognosis of lung adenocarcinoma (LUAD). Epithelial-mesenchymal transition (EMT) process is closely related to tumor cell migration. However, the prognostic value of EMT-related genes in LUAD is still unclear. In this study, we collected bulk RNA-sequencing (RNA-seq) and microarray data of LUAD patients from public databases and identified different expressed EMT-related genes in tumor and normal tissues. Then, we used the least absolute shrinkage and selection operator Cox regression model to develop a multigene signature in the cancer genome atlas (TCGA) cohort and validated the model in the OncoSG (Singapore Oncology Data Portal) cohort as well as other datasets. Finally, we constructed a 12-gene signature to divide LUAD patients into high-risk and low-risk groups of overall survival (OS), which has a better stability and accuracy in predicating the OS of patients compared with some other published signatures of LUAD. In addition, evaluation of the risk model using the time-related receiver operating characteristic (ROC) curve confirmed the predictive ability of the model. Functional analysis showed that these genes are related to immunity. CD8 T cell and CD4 T cell types were significantly negatively correlated with the risk score in the analysis of immune infiltration. In general, our model provides useful information that may help clinicians better predict the prognosis of LUAD patients and provides potential targets for immunotherapy of LUAD.

Identification of Differentially Expressed and Prognostic lncRNAs for the Construction of ceRNA Networks in Lung Adenocarcinoma.

Background Long noncoding RNAs (lncRNAs) could function as competitive endogenous RNAs (ceRNAs) to competitively adsorb microRNAs (miRNAs), thereby regulating the expression of their target protein-coding mRNAs. In this study, we aim to identify more effective diagnostic and prognostic markers for lung adenocarcinoma (LUAD). Methods We obtained differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) for LUAD by using The Cancer Genomes Atlas (TCGA) portal. Weighted gene coexpression network analysis (WGCNA) was performed to unveil core gene modules associated with LUAD. The Cox proportional hazards model was performed to determine the prognostic significance of DElncRNAs. The diagnostic and prognostic significance of DElncRNAs was further verified based on the receiver operating characteristic curve (ROC). Cytoscape was used to construct the ceRNA networks comprising the lncRNAs-miRNAs-mRNAs axis based on the correlation obtained from the miRcode, miRDB, and TargetScan. Results Compared with normal lung tissues, 2355 DElncRNAs, 820 DEmiRNAs, and 17289 DEmRNAs were identified in LUAD tissues. We generated 8 WGCNA core modules in the lncRNAs coexpression network, 5 modules in the miRNAs, and 12 modules in the mRNAs coexpression network, respectively. One lncRNA module (blue) consisting of 441 lncRNAs, two miRNA modules (blue and turquoise) containing 563 miRNAs, and one mRNA module (turquoise), which consisted of 15162 mRNAs, were mostly significantly related to LUAD status. Furthermore, 67 DEmRNAs were found to be tumor-associated as well as the target genes of the DElncRNAs-DEmiRNAs axis. Survival analyses showed that 6 lncRNAs (LINC01447, WWC2-AS2, OGFRP1, LINC00942, LINC01168, and AC005863.1) were significantly correlated with the prognosis of LUAD patients. Ultimately, the potential ceRNA networks including 6 DElncRNAs, 4 DEmiRNAs, and 22 DEmRNAs were constructed. Conclusion Our study indicated that 6 DElncRNAs had the possibilities as diagnostic and prognostic biomarkers for LUAD. The lncRNA-mediated ceRNA networks might provide novel insights into the molecular mechanisms of LUAD progression.

WT1-AS/IGF2BP2 Axis Is a Potential Diagnostic and Prognostic Biomarker for Lung Adenocarcinoma According to ceRNA Network Comprehensive Analysis Combined with Experiments.

Lung adenocarcinoma (LUAD) is one of the most common malignancies, and there is still a lack of effective biomarkers for early detection and prognostic prediction. Here, we comprehensively analyze the characteristics of. an RNA sequencing data set of LUAD samples. In total, 395 long non-coding RNAs (lncRNAs), 89 microRNAs (miRNAs), and 872 mRNAs associated with c-Myc were identified, which were differentially expressed between tumor and normal tissues. The most relevant pathway was found to be WT1-AS–miR-200a-3p–IGF2BP2 according to the rules of competitive endogenous RNA (ceRNA) regulation. WT1-AS and IGF2BP2 expression were positively correlated and increased in LUAD samples, while miR-200a-3p had relatively low expression. The high expression of WT1-AS and IGF2BP2 was associated with poor prognosis in LUAD patients, while low expression of miR-200a-3p predicted reduced survival (p < 0.05). The analysis of the multi-gene regulation model indicated that the WT1-AS (downregulation)–miR-200a-3p (upregulation)–IGF2BP2 (downregulation) pattern significantly improved the survival of LUAD patients. Finally, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were detected in LUAD cells, and the results are consistent with the bioinformatics analysis. In summary, the WT1-AS/IGF2BP2 axis is a potential prognostic biomarker in LUAD and is expected to become an effective target for diagnosis and treatment.

An Immune Panel Signature Predicts Prognosis of Lung Adenocarcinoma Patients and Correlates With Immune Microenvironment.

Background: Lung cancer, especially lung adenocarcinoma (LUAD) with high incidence, seriously endangers human life. The immune microenvironment is one of the malignant foundations of LUAD, but its impact at the molecular level is incompletely understood. Method: A total of 34 LUAD samples from Xiangya Hospital were collected for immune oncology (IO) profiling. Univariate Cox analysis was performed to profile prognostic immune genes based on our immune panel sequencing data. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to construct a risk signature. The cut-off threshold of risk score was determined using X-tile software. Kaplan–Meier survival curves and receiver operating characteristic (ROC) curves were employed to examine the performance of this risk signature for predicting prognosis. The immune infiltration was estimated using a single-sample gene set enrichment analysis (ssGSEA) algorithm. Result: Thirty-seven immune genes were profiled to be significantly correlated with the progression-free survival (PFS) in our cohort. Among them, BST2, KRT7, LAMP3, MPO, S100A8, and TRIM29 were selected to construct a risk signature. Patients with a higher risk score had a significantly shorter PFS (p = 0.007). Time-dependent ROC curves indicated that our risk signature had a robust performance in accurately predicting survival. Specifically, the 6-, 12-, and 18-month area under curve (AUC) was 0.800, 0.932, and 0.912, respectively. Furthermore, the risk signature was positively related to N stage, tumor stage, and tumor malignancy. These results were validated using two external cohorts. Finally, the risk signature was significantly and uniquely correlated with abundance of neutrophil. Conclusion: Our study revealed an immune panel-based signature that could predict the prognosis of LUAD patients and was associated with the infiltration of neutrophils.

A promising prognostic signature for lung adenocarcinoma (LUAD) patients basing on 6 hypoxia-related genes.

Background:Hypoxia signaling plays a critical role in the development of lung adenocarcinoma (LUAD). We herein aimed to explore the prognostic value of hypoxia-related genes and construct the hypoxia-related prognostic signature for LUAD patients.Methods:A total of 26 hypoxia-related genes were collected. Five hundred thirteen and 246 LUAD samples were obtained from the Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. Univariate Cox regression and LASSO Cox regression analyses were conducted to screen the hypoxia-related genes associated with the prognosis of LUAD patients, which would be used for constructing prognosis predictive model for LUAD patients. Multivariate Cox regression analysis was done to determine the independent prognostic factors. The Nomogram model was constructed to predict the prognosis of LUAD patients.Results:Based on 26 hypoxia-related genes, LUAD samples could be divided into 4 clusters with different prognoses. Among which, 6 genes were included to construct the Risk Score and the LUAD patients with higher Risk Score had worse prognosis. Besides, the Nomogram based on all the independent risk factors could relatively reliably predict the survival probability. And 9 types of immune cells’ infiltration was significantly differential between high and low risk LUAD patients.Conclusion:The Risk Score model based on the 6 crucial hypoxia-related genes could relatively reliably predict the prognosis of LUAD patients.

HABP1 promotes proliferation and invasion of lung adenocarcinoma cells through NFκB pathway.

The aim of this research was to investigate the role of hyaluronan-binding protein 1 (HABP1) in lung adenocarcinoma. It was demonstrated by bioinformatics analysis that HABP1 was one of the differentially expressed genes in lung adenocarcinoma. Then, it was confirmed by qPCR, western blot, and immunohistochemistry analysis that HABP1 was upregulated in human tissue specimens we collected. Survival analysis showed that HABP1 was promised to serve as a new biomarker to predict the progress and prognosis of lung adenocarcinoma patients. In addition, we further studied the effects of regulating the expression of HABP1 on lung adenocarcinoma cells, indicating that altered expression of HABP1 could adjust cell proliferation and invasion through the NFκB signaling pathway.

Lung adenocarcinoma-specific three-integrin signature contributes to poor outcomes by metastasis and immune escape pathways.

ABSTRACTBackground:Inhibitors targeting integrins (ITGs) are applied as a novel strategy for cancers including lung cancer; however, the heterogeneity of ITG subunits might explain why ITG-targeted inhibitors only show limited efficacy for a small group of lung cancer patients.Materials and methods:RNA-Seq data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients were obtained from the TCGA database. Cox regression analysis was performed to construct the prognostic signature and generate the nomogram combined with pathologic stages (pStage). GEO datasets were used for verification. The related biological functions were analyzed by Gene Set Enrichment Analysis (GSEA) software and the TIMER database.Results:By Cox regression analysis of 30 ITG subunits, ITG subunit alpha 5 (ITGA5), ITG subunit alpha 6 (ITGA6), and ITG subunit alpha L (ITGAL) were identified as the prognostic factors in LUAD, which were included in the construction of a LUAD-specific 3-ITG signature. Following the calculation of risk score (RS) of each patient based on 3-ITG signature, patients with high RS in LUAD were found to exhibit worse prognosis, especially in early stage. Nomogram combined with RS and pStage could predict the prognosis of LUAD patients accurately. Mechanism exploration by GSEA showed that metastasis-related microenvironmental pathways were significantly enriched in the high-RS group. An elevated expression of ITGA5 was mainly associated with the promotion of cell migration and invasion, while the high expression of ITGAL had a strong positive correlation with the capability of recognizing and killing cancer cells.Conclusions:Three-ITG signature could improve the prediction ability combined with pStage in LUAD and might contribute to poor prognosis by metastasis and immune escape-related pathways.

Correlation of ARNTL2 with Immune Infiltration and Its Role as a Potential Prognostic Biomarker in Lung Adenocarcinoma

ARNTL2 is a core component of the circadian clock genes and plays regulatory roles in the cell cycle and immune infiltration, but its mechanism in lung cancer (LC) remains unclear. To investigate the clinical and therapeutic value of ARNTL2 in LC. The Oncomine and Cancer Cell Line Encyclopedia (CCLE) databases were adopted for assessing the ARNTL2 expression, after which the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases were used to assess the correlation of ARNTL2 with prognosis. The univariate and multivariate Cox regression analyses were utilized to identify independent prognostic factors. Also, we explored how ARNTL2 expression is related to immune infiltration, and immunomodulators in non-small lung cancer (NSCLC) using the Tumor Immune Estimation Resource (TIMER) database, TISIDB database and Gene Set Enrichment Analysis (GSEA). Finally, coexpression of ARNTL2 and PD-L1 in lung adenocarcinoma (LUAD) was verified via immunofluorescence staining and COXPRESdb v7 database. Our study demonstrated a remarkable upregulated expression of ARNTL2 in multiple cell lines and cancers, including NSCLC. Prognostic analysis displayed a remarkable correlation between high ARNTL2 expression and unfavorable overall survival (OS) and first progressive (FP) survival among patients ailing from LUAD, and ARNTL2 was an independent predictor of prognosis for LUAD patients. GSEA analysis showed that overexpression of ARNTL2 was significantly linked with cell cycle and immunity. Furthermore, we reported a correlation of ARNTL2 expression with immunomodulators and lymphocytes. Immunofluorescence staining revealed that ARNTL2 and PD-L1 were elevated relative to normal tissue for LUAD, and colocalization of them was observed. Elevated ARNTL2 expression in LUAD revealed the prognostic values and its prospective role as a target for cell cycle and immune therapy.

Prognostic value of SEC61G in lung adenocarcinoma: a comprehensive study based on bioinformatics and in vitro validation

BackgroundStudies have shown that the Sec61 gamma subunit (SEC61G) is overexpressed in several tumors and could serve as a potential prognostic marker. However, the correlation between SEC61G and lung adenocarcinoma (LUAD) remains unclear. In the current study, we aimed to demonstrate the prognostic value and potential biological function of the SEC61G gene in LUAD.MethodsPublic datasets were used for SEC61G expression analyses. The prognostic value of SEC61G in LUAD was investigated using the Kaplan–Meier survival and Cox analyses. The correlation between the methylation level of SEC61G and its mRNA expression was evaluated via cBioPortal. Additionally, MethSurv was used to determine the prognostic value of the SEC61G methylation levels in LUAD. Functional enrichment analysis was conducted to explore the potential mechanism of SEC61G. Also, single sample GSEA (ssGSEA) and TIMER online tool were applied to identify the correlation between SEC61G and immune filtration. Furthermore, cell functional experiments were conducted to verify the biological behavior of SEC61G in lung adenocarcinoma cells (LAC).ResultsSEC61G was upregulated in pan-cancers, including LUAD. High SEC61G expression was significantly correlated with worse prognosis in LUAD patients. Multivariate analysis demonstrated that high SEC61G expression was an independent prognostic factor in the TCGA cohort. (HR = 1.760 95% CI: 1.297–2.388, p < 0.001). The methylation level of SEC61G negatively correlated with the SEC61G expression (R = − 0.290, p < 0.001), and patients with low SEC61G methylation had worse overall survival. (p = 0.0014). Proliferation-associated terms such as cell cycle and cell division were significantly enriched in GO and KEGG analysis. Vitro experiments demonstrated that knockdown of SEC61G resulted in decreased cell proliferation, invasion and facilitated apoptosis in LAC. GSEA analysis found that SEC61G expression was associated with the E2F targets. Moreover, SEC61G expression was negatively correlated with the immune cell infiltration including CD4+ T cell, CD8+ T cell, B cell, macrophage, neutrophil, and dendritic cell.ConclusionOur study indicated that overexpression of SEC61G was significantly associated with poor prognosis of LUAD patients and the malignant phenotypes of LUAD cells, suggesting that it could be a novel prognostic biomarker and potential therapeutic target of LUAD.

MiR-21-5p is a Biomarker for Predicting Prognosis of Lung Adenocarcinoma by Regulating PIK3R1 Expression.

BackgroundLung cancer (LUCA) is one of the most prevalent human malignancies, and the leading cause of cancer-related deaths worldwide. Previous reports have shown that miR-21-5p plays a vital role in development of various tumors. Here, we explored the relationship between miR-21-5p/PIK3R1 axis and prognosis of patients with lung adenocarcinoma (LUAD).MethodsMiRNAseq data, deposited in The Cancer Genome Atlas (TCGA) database, was downloaded and used to determine patterns of miR-21-5p expression in both LUAD and normal lung tissues. Statistical analyses and data visualization were performed using dbDEMC v3.0 platform, starBase v3.0 database and packages implemented in R software. Next, we employed TargetScan Human, miRDB and DIANA Tools databases to predict miR-21-5p target genes, then analyzed their expression patterns as well as prognostic value in LUAD.FindingsMost human cancers overexpressed miR-21-5p. Specifically, miR-21-5p was significantly upregulated in LUAD tissues relative to normal lung tissues (P < 0.001), and this high expression was significantly correlated with poor patient prognosis (hazard ratio [HR]=1.45, P = 0.014). PIK3R1 was predicted as a miR-21-5p target gene, and both were negatively correlated (r=−0.218, P < 0.01). Notably, PIK3R1 was significantly downregulated in LUAD, relative to normal lung tissues (P < 0.01), with its overexpression significantly associated with poor prognosis of LUAD patients (HR = 0.62, P = 0.0014).ConclusionmiR-21-5p is a potential prognostic biomarker for LUAD patients. Moreover, it might be playing a role in LUAD progression by regulating PIK3R1 expression.

A Novel Predictive Model Incorporating Ferroptosis-Related Gene Signatures for Overall Survival in Patients with Lung Adenocarcinoma.

BackgroundLung adenocarcinoma (LUAD) is the predominant histological type of lung cancer with high morbidity and mortality. Ferroptosis is regarded as a new pattern of programmed cell death concerned with the progression of lung cancer characterized by lipid peroxidation. Nevertheless, the prognostic role of ferroptosis-related genes for LUAD warrant to be explored.Material/MethodsRNA sequencing and relevant clinical patient data were obtained from public-access databanks. A prognostic model was constructed through the LASSO Cox regression in the cancer genome atlas cohort. The diagnostic value of the prognostic model was further evaluated in the gene expression omnibus cohort.ResultsMost of the ferroptosis-related genes (69.9%) were differentially expressed between tumor and adjacent non-cancerous tissues. 43 differentially expressed genes showed a close association with the prognosis of LUAD patients (adjusted p-value <0.05). An 18-gene signature was built and applied to assign patients into high vs low-risk groups. Compared with the high-risk group, patients defined as the low-risk group suffered significantly prolonged OS. Both uni- and multivariate analyses demonstrated that the signature-based score served as a crucial role in influencing the OS of LUAD patients (hazard ratio >1, p<0.001). The immunity-related signaling pathway was enriched in the functional analysis and the infiltration of the immune cells showed a great difference between groups.ConclusionsThe predictive model could be applied for prognostic prediction for LUAD. Targeting ferroptosis could be a possible curative strategy against LUAD, and immunomodulation may be one of the potential mechanisms.

Relationships of N6-Methyladenosine-Related Long Non-Coding RNAs With Tumor Immune Microenvironment and Clinical Prognosis in Lung Adenocarcinoma

Background: Lung adenocarcinoma (LUAD) is the major subtype of lung cancer and is associated with very high mortality. Emerging studies have shown that N6-methyladenosine (m6A)-related long non-coding (lnc) RNAs play crucial roles in tumor prognosis and the tumor immune microenvironment (TME). We aimed to explore the expression patterns of different m6A-related lncRNAs concerning patient prognosis and construct an m6A-related lncRNA prognostic model for LUAD. Methods: The prognostic value of m6A-related lncRNAs was investigated in LUAD samples from The Cancer Genome Atlas (TCGA). Potential prognostic m6A-related lncRNAs were selected by Pearson’s correlation and univariate Cox regression analysis. Patients were divided into clusters using principal component analysis and the m6A-related lncRNA prognostic signature was calculated using least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Results: Based on 91 prognostic m6A-related lncRNAs, we identified two m6A-related-lncRNA pattern clusters with different overall survival (OS) and different TMEs. We subsequently verified our findings multidimensionally by constructing a 13 m6A-related lncRNA prognostic signature (m6A-LPS) to calculate the risk score, which was robust in different subgroups. The receiver operating characteristic (ROC) curves and concordance index demonstrated that m6A-LPS harbored a promising ability to predict OS in TCGA data set and independent GSE11969 cohort. The risk score was also related to OS, TME, and clinical stage, and the risk score calculated by our model was also identified as independent prognostic predictive factors for LUAD patients after adjustment for age, smoking, gender, and stage. Enrichment analysis indicated that malignancy and drug resistance-associated pathways were more common in cluster2 (LUAD-unfavorable m6A-LPS). Furthermore, the results indicated that the signaling pathway enriched by the target gene of 13 m6A-related lncRNAs may be associated with metastasis and progression of cancer according to current studies. Conclusion: The current results indicated that different m6A-related-lncRNA patterns could affect OS and TME in patients with LUAD, and the prognostic signature based on 13 m6A-related lncRNAs may help to predict the prognosis in LUAD patients.

CRMP2 as a Candidate Target to Interfere with Lung Cancer Cell Migration.

Collapsin response mediator protein 2 (CRMP2) is an adaptor protein that adds tubulin dimers to the growing tip of a microtubule. First described in neurons, it is now considered a ubiquitous protein that intervenes in processes such as cytoskeletal remodeling, synaptic connection and trafficking of voltage channels. Mounting evidence supports that CRMP2 plays an essential role in neuropathology and, more recently, in cancer. We have previously described a positive correlation between nuclear phosphorylation of CRMP2 and poor prognosis in lung adenocarcinoma patients. In this work, we studied whether this cytoskeleton molding protein is involved in cancer cell migration. To this aim, we evaluated CRMP2 phosphorylation and localization in the extending lamella of lung adenocarcinoma migrating cells using in vitro assays and in vivo confocal microscopy. We demonstrated that constitutive phosphorylation of CRMP2 impaired lamella formation, cell adhesion and oriented migration. In search of a mechanistic explanation of this phenomenon, we discovered that CRMP2 Ser522 phospho-mimetic mutants display unstable tubulin polymers, unable to bind EB1 plus-Tip protein and the cortical actin adaptor IQGAP1. In addition, integrin recycling is defective and invasive structures are less evident in these mutants. Significantly, mouse xenograft tumors of NSCLC expressing CRMP2 phosphorylation mimetic mutants grew significantly less than wild-type tumors. Given the recent development of small molecule inhibitors of CRMP2 phosphorylation to treat neurodegenerative diseases, our results open the door for their use in cancer treatment.

Construction and analysis of a novel ferroptosis-related gene signature predicting prognosis in lung adenocarcinoma.

Ferroptosis is a newly discovered, iron‐dependent, nonapoptotic form of programmed cell death that plays an important role in the development of lung adenocarcinoma (LUAD). In this study, ferroptosis‐related genes (FRGs) were identified from the FerrDb dataset, and the mRNA expression profiles and corresponding clinical data of LUAD patients were downloaded from the University of California, Santa Cruz (UCSC) databases. Data from LUAD patients from the Gene Expression Omnibus (GEO) dataset were used as the verification set. Cox and Lasso regression analyses were used to screen the FRGs with prognostic value, and six prognostic‐related FRGs were selected to construct prognostic risk score signatures. Immunohistochemistry was utilized to manifest the differential expression of six FRGs in tumor and normal tissues at the protein level. Functional enrichment analysis indicated that FRGs were mainly enriched in ferroptosis‐related pathways. Patients were divided into high‐ and low‐risk groups based on the median risk score. The Kaplan–Meier survival curves confirmed that patients with a high score had significantly worse overall survival. Receiver operating characteristic (ROC) curves proved that the prognostic signature has good sensitivity and specificity for predicting the prognosis of LUAD patients. Nomogram analysis showed that the prognostic signature has potential independent prognostic value. Moreover, the prognostic signature has been shown to be significantly associated with some clinical features (T stage, N stage, tumor stage, and survival status) as well as many immune‐activity‐related genes and immune‐checkpoint‐related genes. In conclusion, we constructed a prognostic signature consisting of six FGRs, which can provide a reference for predicting the prognosis of LUAD patients.

Identification of critical ferroptosis regulators in lung adenocarcinoma that RRM2 facilitates tumor immune infiltration by inhibiting ferroptotic death

Ferroptosis is a novel form of cell death characterized by heavy iron accumulation and lipid peroxidation that plays a critical role in the tumor microenvironment. However, promising biomarkers associated with tumor immune cell infiltration and the immunotherapy response to ferroptosis regulators remain to be elucidated in lung adenocarcinoma (LUAD) patients. In this study, we defined ferroptosis regulators in LUAD through database analysis and experimental validation to determine the implementation of genes associated with clinical relevance, immunotherapy response and tumor microenvironment in LUAD patients. Multiomics data analysis was performed to explore the CNV features, molecular mechanisms and immunogenic characteristics of ferroptosis regulators in LUAD patients. Then, univariate and multivariate Cox regression analyses were used to identify three genes (DDIT4, RRM2, and SLC2A1) that were closely associated with the prognosis of LUAD patients. The prognostic model based on the determination of these three genes was an independent prognostic factor (p < 0.05, HR = 2.838), and patients with superior predictive performance and higher prognostic risk were more likely to have poor survival rates than those with lower prognostic risk in the training group (p < 0.001, HR = 3.19) and the test group (p < 0.001, HR = 2.94; p < 0.001, HR = 3.44). Activated immune cells, including T helper cells and activated CD8 T cells, were lower in the high-risk group, while type 2 T cells were higher (p < 0.05). Patients with higher prognostic risk were less likely to benefit from immunotherapy, partly due to low CTLA4 levels and an immunosuppressive microenvironment (p < 0.05). Combined with LUAD tissue samples and mouse trials, RRM2 was found to influence lung cancer progression and affect tumor immune cell infiltration. RRM2 inhibition effectively promoted M1 macrophage polarization and suppressed M2 macrophage polarization in vitro and in vivo. And ferroptosis inhibitor ferrostatin-1 treatment effectively re-blanced macrophage polarization mediated by RRM2 inhibition. Taken together, the results of the multiomics data analysis and experimental validation identified ferroptosis regulators as promising biomarkers and therapeutic targets associated with tumor immune infiltration in LUAD patients.

The Pro-Survival Oct4/Stat1/Mcl-1 Axis Is Associated with Poor Prognosis in Lung Adenocarcinoma Patients.

The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that they can proliferate indefinitely, leading to ineffective therapy for cancer patients. In this study, we investigated whether Oct4 regulates the apoptosis pathway and contributes to poor prognosis in patients with lung adenocarcinoma. Our results revealed that Oct4 expression is correlated with Stat1 expression in lung adenocarcinoma patients and Oct4 is directly bound to the Stat1 promoter to transactivate Stat1 in lung adenocarcinoma cells. Expression of the Stat1 downstream gene Mcl-1 increased in Oct4-overexpressing cancer cells, while Stat1 knockdown in Oct4-overexpressing cancer cells sensitized them to cisplatin-induced apoptosis. Furthermore, Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 reduced Oct4-induced tumor growth in human lung tumor xenograft models. Taken together, we demonstrate that Oct4 is a pro-survival factor by inducing Stat1 expression and that the Oct4/Stat1/Mcl-1 axis may be a potential therapeutic target for lung adenocarcinoma.

The roles of risk model based on the 3-XRCC genes in lung adenocarcinoma progression.

BackgroundThe abnormal expression of deoxyribonucleic acid (DNA) repair genes might be the cause of tumor development and resistance of malignant cells to chemotherapeutic drugs. A risk model based on the X-ray repair of cross-complementary (XRCC) genes was constructed to improve the diagnosis and treatment of lung adenocarcinoma (LUAD) patients.MethodsThe expression levels, diagnostic values, and prognostic values of XRCC genes were identified, and the roles and regulatory mechanisms of the risk model based on the XRCC4/5/6 in LUAD progression was explored via The Cancer Genome Atlas (TCGA) and Oncomine databases.ResultsXRCC1/2/3/4/5/6, XRCC7 (PRKDC), and XRCC9 (FANCG) were overexpressed, and had diagnostic value for LUAD. The XRCC genes were involved in DNA repair, and participated in the regulation of non-homologous end-joining, homologous recombination, etc. The overall survival (OS), tumor (T) stage, and survival status of patients were significantly different between the Cluster1 and Cluster2 groups. XRCC4/5/6 were independent risk factors affecting the prognosis of LUAD patients. The risk score was related to the prognosis, sex, clinical stage, T, lymph node (N), and metastasis (M) stage, as well as the survival status of LUAD patients. The clinical stage and risk score were independent risk factors for poor prognosis in LUAD patients. The risk model was involved in RNA degradation, cell cycle, basal transcription factors, DNA replication etc. The risk scores were significantly correlated with the expression levels of TGFBR1, CD160, TNFSF4, TNFRSF14, IL6R, CXCL16, TNFRSF25, TAPBP, CCL16, and CCL14.ConclusionsThe risk model based on the XRCC4/5/6 genes could predict the progression of LUAD patients.

Prognostic significance of HSF2BP in lung adenocarcinoma.

BackgroundRecent studies have demonstrated that upregulation of heat shock transcription factor 2 binding protein (HSF2BP) may promote genomic instability, thereby leading to the development of tumors and also providing a potential target for biological antitumor therapy. However, the role of HSF2BP has so far remained unclear in lung adenocarcinoma (LUAD).MethodsTo explore the function of HSF2BP in LUAD, we collected transcriptome data for 551 lung samples from The Cancer Genome Atlas (TCGA) database and methylation data for 461 lung samples from the University of California Santa Cruz (UCSC) genome database, in addition to corresponding clinical information. We used bioinformatic approaches to systematically explore the role of HSF2BP in LUAD, including Gene Set Enrichment Analysis (GSEA), coexpression analysis, the Tumor IMmune Estimation Resource (TIMER) tool, Connectivity Map (CMap) analysis, and a meta-analysis involving three Gene Expression Omnibus (GEO) datasets and one TCGA dataset.ResultsOur results found that upregulation of HSF2BP in LUAD was an independent risk factor for the prognosis and diagnosis of LUAD. GSEA analysis showed HSF2BP expression was associated with vital signaling pathways, including the cell cycle, P53 signaling pathway, and homologous recombination. Coexpression analysis revealed 10 HSF2BP-associated genes, including oncogenes and tumor suppressor genes. Additionally, we found that HSF2BP expression was negatively correlated with B-cell infiltration and had a potential interaction with CD80 in LUAD, which may play an important role in tumor immune escape. Finally, we identified four small-molecule drugs which show promise for LUAD treatment.ConclusionsThe present study found that elevated HSF2BP posed a threat to prognosis in LUAD patients. HSF2BP might have been involved in tumorigenesis by influencing genomic stability and contributing to tumor immune evasion in the tumor immune microenvironment of LUAD. These findings suggest that HSF2BP may provide a vulnerable target for improving and enhancing treatment of LUAD.

P70.06 m6A reader IGF2BP1 High Protein Expression level Indicates a Poor Recovery for Lung Adenocarcinoma Patients

Previous studies we found that IGFII mRNA-binding protein 1 (IGF2BP1) were highly expressed in Lung Adenocarcinoma (LUAD) patients tumor tissues compared with normal lung tissues and high expression related to LUAD various clinical pathological stages in transcription level[Wang, X. , et al. WCLC2020 ]. In this study, we analyzed in the translation level of patients with LUAD , in order to further obtain the impact of IMP1 on the prognosis of LUAD patients. In order to evaluate the differential expression and prognosis value of IGF2BP1 in LUAD, a tissue microarray (TMA) (LUC1601) containing 80 pair LUAD tumor tissues and paratumor tissues with overall survival rate follow-up, detailed TNM staging information was obtained from Superbiotek (Shanghai, China). Standard Immunohistochemical methods were used to detect the expression of IGF2BP1 in paraffin specimens of each samples. Aperio ImageScope viewing software were used for analyzing Immunohistochemical intensity created by the Aperio scanner for the TMA. Then the clinical role of IGF2BP1 Immunohistochemical intensity on the overall survival of LUAD patients was illustrated by multivariate Cox hazards regression and Kaplan-Meier analysis. IGF2BP1 Immunohistochemical analysis demonstrated that LUAD tumor tissues was highly stained comparable with normal paratumor tissues. According to the immunohistochemistry score the tumor samples were divided into two groups with a score = 1.2 as cut off and 56 tumor samples were highly stained. Kaplan-Meier analysis showed that high score group patients owned poorer overall survival than patients with low stained samples and more than 50 percent of low risk patients survived during the follow-up period (> 7 years). Due to the low sample size, the multivariate analysis shows that IGF2BP1 is not an independent prognostic factor, which may also be related to the influence of IGFBP1 on clinical staging. Our study found that highly IGF2BP1 protein level heralds a poor prognosis in LUAD. These results provides new clinical evidence for the role of IGF2BP1 on LUAD and may lay a theoretical foundation for LUAD corresponding countermeasures.