Functions In Lung Adenocarcinoma Research Articles

CacyBP promotes the development of lung adenocarcinoma by regulating OTUD5.

Lung cancer is the most common and lethal malignancy, with lung adenocarcinoma accounting for approximately 40% of all cases. Despite some progress in understanding the pathogenesis of this disease and developing new therapeutic approaches, the current treatments for lung adenocarcinoma remain ineffective due to factors such as high tumour heterogeneity and drug resistance. Therefore, there is an urgent need to identify novel therapeutic targets. CacyBP can regulate a variety of physiological processes by binding to different proteins, but its function in lung adenocarcinoma is unknown. Here, we show that CacyBP is highly expressed in lung adenocarcinoma tissues, and high CacyBP expression correlates with poorer patient survival. Moreover, overexpression of CacyBP promoted the proliferation, migration and invasion of lung adenocarcinoma cell lines. Further mechanistic studies revealed that CacyBP interacts with the tumour suppressor OTUD5, enhances the ubiquitination and proteasomal degradation of OTUD5, and regulates tumorigenesis via OTUD5. In conclusion, our study reveals a novel mechanism by which CacyBP promotes tumorigenesis by increasing the ubiquitination level and proteasome-dependent degradation of OTUD5, providing a potential target for the treatment of lung adenocarcinoma.

IGSF10 inhibits the metastasis of lung adenocarcinoma via the Spi-B/Integrin-β1 signaling pathway.

IGSF10, a protein that belongs to the immunoglobulin superfamily, is involved in regulating the early migration of neurons that produce gonadotropin-releasing hormoneand performs a fundamental function in development. Our previous study confirmed that the mRNA expression level of IGSF10 may be a protective prognosis factor for lung adenocarcinoma (LUAD) patients. However, the specific mechanisms of IGSF10 are still unclear. In this research, it was shown that the protein level of IGSF10 was down-modulated in LUAD tissues and had a link to the clinical and pathological characteristics as well as the patient's prognosis in LUAD. Importantly, IGSF10 regulates the metastatic ability of LUAD cells in vitro and in vivo. It was proven in a mechanistic sense that IGSF10 inhibits the capacity of LUAD cells to metastasize through the Spi-B/Integrin-β1 signaling pathway. These findings gave credence to the premise that IGSF10 performed a crucial function in LUAD.

Integrative single-cell analysis of LUAD: elucidating immune cell dynamics and prognostic modeling based on exhausted CD8+ T cells.

The tumor microenvironment (TME) plays a pivotal role in the progression and metastasis of lung adenocarcinoma (LUAD). However, the detailed characteristics of LUAD and its associated microenvironment are yet to be extensively explored. This study aims to delineate a comprehensive profile of the immune cells within the LUAD microenvironment, including CD8+ T cells, CD4+ T cells, and myeloid cells. Subsequently, based on marker genes of exhausted CD8+ T cells, we aim to establish a prognostic model for LUAD. Utilizing the Seurat and Scanpy packages, we successfully constructed an immune microenvironment atlas for LUAD. The Monocle3 and PAGA algorithms were employed for pseudotime analysis, pySCENIC for transcription factor analysis, and CellChat for analyzing intercellular communication. Following this, a prognostic model for LUAD was developed, based on the marker genes of exhausted CD8+ T cells, enabling effective risk stratification in LUAD patients. Our study included a thorough analysis to identify differences in TME, mutation landscape, and enrichment across varying risk groups. Moreover, by integrating risk scores with clinical features, we developed a new nomogram. The expression of model genes was validated via RT-PCR, and a series of cellular experiments were conducted, elucidating the potential oncogenic mechanisms of GALNT2. Our study developed a single-cell atlas for LUAD from scRNA-seq data of 19 patients, examining crucial immune cells in LUAD's microenvironment. We underscored pDCs' role in antigen processing and established a Cox regression model based on CD8_Tex-LAYN genes for risk assessment. Additionally, we contrasted prognosis and tumor environments across risk groups, constructed a new nomogram integrating clinical features, validated the expression of model genes via RT-PCR, and confirmed GALNT2's function in LUAD through cellular experiments, thereby enhancing our understanding and approach to LUAD treatment. The creation of a LUAD single-cell atlas in our study offered new insights into its tumor microenvironment and immune cell interactions, highlighting the importance of key genes associated with exhausted CD8+ T cells. These discoveries have enabled the development of an effective prognostic model for LUAD and identified GALNT2 as a potential therapeutic target, significantly contributing to the improvement of LUAD diagnosis and treatment strategies.

Exploring the Diagnostic and Prognostic Predictive Values of Ferroptosis- Related Markers in Lung Adenocarcinoma.

Lung Adenocarcinoma (LUAD), a common and aggressive form of lung cancer, poses significant treatment challenges due to its low survival rates. To better understand the role of ferroptosis driver genes in LUAD, this study aimed to explore their diagnostic and prognostic significance, as well as their impact on treatment approaches and tumor immune function in LUAD. To accomplish the defined goals, a comprehensive methodology incorporating both in silico and wet lab experiments was employed. A comprehensive analysis was conducted on a total of 233 ferroptosis driver genes obtained from the FerrDB database. Utilizing various TCGA databases and the RT-qPCR technique, the expression profiles of 233 genes were examined. Among them, TP53, KRAS, PTEN, and HRAS were identified as hub genes with significant differential expression. Notably, TP53, KRAS, and HRAS exhibited substantial up-regulation, while PTEN demonstrated significant down-regulation at both the mRNA and protein levels in LUAD samples. The dysregulation of hub genes was further associated with poor overall survival in LUAD patients. Additionally, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed aberrant promoter methylation patterns linked to the dysregulation of hub genes. Furthermore, hub genes were found to participate in diverse oncogenic pathways, highlighting their involvement in LUAD tumorigenesis. By leveraging the diagnostic and prognostic potential of ferroptosis driver hub genes (TP53, KRAS, PTEN, and HRAS), significant advancements can be made in the understanding and management of LUAD pathogenesis. Therapeutic targeting of these genes using specific drugs holds great promise for revolutionizing drug discovery and improving the overall survival of LUAD patients.

TMEM158 functions as an oncogene and promotes lung adenocarcinoma progression through the PI3K/AKT pathway via interaction with TWIST1

Lung adenocarcinoma (LUAD) is a common and deadly form of lung cancer, with high rates of metastasis and unsatisfactory clinical outcomes. Herein, we examined the influence of TMEM158 on the LUAD progression. A combination of bioinformatic analyses was used to assess the TMEM158 expression pattern, prognostic implications, and potential function in LUAD. The levels of TMEM158 and TWIST1 were evaluated in clinical samples from LUAD patients using Western blot analysis and qRT-PCR. To discover the function and underlying molecular pathways of TMEM158 in LUAD, we employed a combination of experimental approaches in vitro, such as flow cytometry analysis and colony formation, Co-IP, CCK-8, Transwell, and wound-healing assays. Elevated expression of TMEM158 in LUAD is associated with increased cancer aggressiveness and a poor prognosis. In vitro experiments demonstrated that high levels of TMEM158 promote cell proliferation, progression through the cell cycle, migration, and invasion while suppressing apoptosis. Knockdown of TMEM158 produced opposite effects. The underlying mechanism involves TMEM158 and TWIST1 directly interacting, stimulating the PI3K/AKT signaling pathway in LUAD cells. This investigation emphasizes the molecular functions of TMEM158 in LUAD progression and proposes targeting it as a promising treatment approach for managing LUAD.

Anti-cancer effects of Coix seed extract through KCTD9-mediated ubiquitination of TOP2A in lung adenocarcinoma

BackgroundCoix seed extract (CSE), a traditional Chinese medicine, has been reported as an adjunctive therapy in cancers. However, the molecular targets are largely unclear. The study is designed to unveil its function in lung adenocarcinoma (LUAD) and the possible molecular mechanism.MethodsThe HERB database was utilized to predict the molecular targets of the Coix seed, followed by prognostic value prediction in the Kaplan–Meier Plotter database. LUAD cells were infected with sh-KCTD9 after co-culture with CSE, and cell viability, growth, proliferation, and apoptosis were determined. The substrates of KCTD9 were predicted using a protein–protein interaction network and verified. The expression of PD-L1, the contents of TNF-α, IFN-γ, CXCL10, and CXCL9 in the co-culture system of LUAD cells and T cells and the proliferation of T cells were evaluated to study the immune escape of LUAD cells in response to CSE and sh-KCTD9. Lastly, tumor growth and immune escape were observed in tumor-bearing mice.ResultsCSE inhibited malignant behavior and immune escape of LUAD cells, and the reduction of KCTD9 reversed the inhibitory effect of CSE on malignant behavior and immune escape of LUAD cells. Knockdown of KCTD9 expression inhibited ubiquitination modification of TOP2A, and knockdown of TOP2A suppressed immune escape of LUAD cells in the presence of knockdown of KCTD9. CSE exerted anticancer effects in mice, but the reduction of KCTD9 partially compromised the anticancer effect of CSE.ConclusionCSE inhibits immune escape and malignant progression of LUAD through KCTD9-mediated ubiquitination modification of TOP2A.

Cuproptosis Related Gene DLD Associated with Poor Prognosis and Malignant Biological Characteristics in Lung Adenocarcinoma.

Cuproptosis plays a crucial role in the biological function of cells. The subject of this work was to analyze the effects of cuproptosis-related genes (CRGs) on the prognosis and biological function in lung adenocarcinoma (LUAD). In this study, RNA sequencing and clinical data of LUAD samples were screened from public databases and our institution. A CRG signature was identified by least absolute shrinkage and selection operator and Cox regression. In addition, this study analyzed the correlation between prognostic CRGs and clinicopathological features. Finally, this study studied the effect of inhibiting dihydrolipoamide dehydrogenase (DLD) expression on cell biological function. There were 10 CRGs that showed differential expression between LUAD and normal tissues (p<0.05). A prognostic signature (DLD and lipoyltransferase 1 [LIPT1]) was constructed. Survival analysis suggested that patients with LUAD in the high-risk group had shorter overall survival (OS) (p<0.05). High expression of DLD and low expression of LIPT1 were significantly associated with shorter OS (p<0.05). Immunohistochemical analysis revealed that, in LUAD tissues, DLD was highly expressed, whereas LIPT1 was not detected. Finally, inhibition of DLD expression could significantly restrain cell proliferation, invasion and migration. Overall, this prognostic CRG signature may play a pivotal role in LUAD outcome, while oncogene DLD may be a future therapeutic candidate for LUAD.

Immune, metabolic landscapes of prognostic signatures for lung adenocarcinoma based on a novel deep learning framework

Lung adenocarcinoma (LUAD) is a malignant tumor with high lethality, and the aim of this study was to identify promising biomarkers for LUAD. Using the TCGA-LUAD dataset as a discovery cohort, a novel joint framework VAEjMLP based on variational autoencoder (VAE) and multilayer perceptron (MLP) was proposed. And the Shapley Additive Explanations (SHAP) method was introduced to evaluate the contribution of feature genes to the classification decision, which helped us to develop a biologically meaningful biomarker potential scoring algorithm. Nineteen potential biomarkers for LUAD were identified, which were involved in the regulation of immune and metabolic functions in LUAD. A prognostic risk model for LUAD was constructed by the biomarkers HLA-DRB1, SCGB1A1, and HLA-DRB5 screened by Cox regression analysis, dividing the patients into high-risk and low-risk groups. The prognostic risk model was validated with external datasets. The low-risk group was characterized by enrichment of immune pathways and higher immune infiltration compared to the high-risk group. While, the high-risk group was accompanied by an increase in metabolic pathway activity. There were significant differences between the high- and low-risk groups in metabolic reprogramming of aerobic glycolysis, amino acids, and lipids, as well as in angiogenic activity, epithelial-mesenchymal transition, tumorigenic cytokines, and inflammatory response. Furthermore, high-risk patients were more sensitive to Afatinib, Gefitinib, and Gemcitabine as predicted by the pRRophetic algorithm. This study provides prognostic signatures capable of revealing the immune and metabolic landscapes for LUAD, and may shed light on the identification of other cancer biomarkers.

Comprehensive analysis of prognostic value and immune infiltration of Regulator of Chromosome Condensation 2 in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) incidence and mortality take the leading place of most malignancies. Previous studies have revealed the regulator of chromosome condensation 1 (RCC1) family members played an essential role during tumorigenesis. However, its biological functions in LUAD still need further investigation. Methods: Several databases were applied to explore potential effects of RCC1 family members on LUAD, such as Oncomine, GEPIA, and cBioPortal. Real-time PCR and immunohistochemistry were used to verify the expression of RCC2 in stage I LUAD. H1975 and A549 were selected to explore the biological function of RCC2 in cellular malignant phenotype. Results: The expressions of RCC1 and RCC2 showed marked differences in malignant tissue compared to lung tissue. The higher the expression levels of RCC1 or RCC2 in LUAD patients, the shorter their overall survival (OS). In normal lung tissues, RCC1 expression was highly enriched in alveolar cells and endothelial cells. Compare with RCC1, RCC2 expression in normal lung tissue was significantly enriched in macrophages, B cells and granulocytes. Additionally, RCC2 expression level was correlated with multiple immune cell infiltration in LUAD. Moreover, the mutation or different sCNA status of RCC2 exerted influence on multiple immune cell infiltration distribution. We found that the upregulation of RCC1 and RCC2 were obviously related to TP53 mutation. GSEA analysis revealed that RCC2 was involved in the process of DNA replication, nucleotide excision repair and cell cycle, which might affect tumor progression through P53 signaling pathway. We further elucidated that downregulation of RCC2 could dramatically repress the migration and invasion of LUAD cells. Conclusions: The study demonstrated that RCC1 and RCC2 expression were markedly increased in early-stage of LUAD. Patients with high expression of RCC1 or RCC2 had a worse prognosis. Based on our analysis, RCC1 and RCC2 might exert influence on LUAD process through DNA replication, nucleotide excision repair and cell cycle, as well as cells migration and invasion. Different from RCC1, RCC2 also involved in immune infiltration. These analyses provided a novel insight into the identification of diagnostic biomarker.

Identification of an Exosome-relevant SNHG6-hsa-miR-429- CHRDL1/CCNA2 Axis for Lung Adenocarcinoma Prognosis Evaluation

aims: To explore exosome gene-driven competitive endogenous RNA networks in lung adenocarcinoma (LUAD). background: Exosome genes or non-coding RNAs within them are regulators of cancer treatment and prognosis, but their function in LUAD has not yet been determined. objective: Unraveling a molecular classification applying exosome-related RNA networks for LUAD prognosis evaluation. method: MicroRNA sequencing data (miRNAs-seq) and RNA sequencing data (RNA- seq) were derived from The Cancer Genome Atlas (TCGA). The ConsensusCluster- Plus package was used for molecular typing in LUAD based on 121 Exosome-related genes. Then, a limma package was conducted to explore differentially expressed mRNAs (DEmRNAs), differentially expressed miRNAs (DEmiRNAs) and differentially expressed lncRNAs (DElncRNAs) in molecular typing for constructing an Exosome-driven competing endogenous RNA network (ceRNA). Dominant miRNAs, as well as target mRNAs, were identified by COX modeling and Kaplan-Meier survival analysis. result: Two Exosome-associated molecular clusters classified in LUAD. The C2 cluster favored high clinicopathology and showed a trend toward poor prognosis. 29 lncRNA- miRNA and 12 miRNA-mRNA interaction pairs were identified. The hsa-miR-429 was the pivotal miRNA in the network that affected the prognosis of LUAD. According to the interaction relationship and LUAD prognostic role, SNHG6-hsa- miR-429-CHRDL1/CCNA2 was identified. SNHG6-hsa-miR-429-CHRDL1 exerts oncogenic effects, and SNHG6-hsa-miR-429- CCNA2 exerts pro-oncogenic effects. conclusion: Overall, our study identified an Exosome-driven ceRNA network in LUAD, and the SNHG6-hsa-miR-429-CHRDL1/CCNA2 axis could be a new therapeutic target for LUAD and our study provides new insights into the molecular mechanisms of LUAD.

[Identification of SULF1 as a Shared Gene in Idiopathic Pulmonary Fibrosis
and Lung Adenocarcinoma].

Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer. Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases. A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts. This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.

TAGAP expression influences CD4+ T cell differentiation, immune infiltration, and cytotoxicity in LUAD through the STAT pathway: implications for immunotherapy.

T-cell Activation GTPase Activating Protein (TAGAP) plays a role in immune cell regulation. This study aimed to investigate TAGAP's expression and its potential impact on CD4+ T cell function and prognosis in lung adenocarcinoma (LUAD). We analyzed TAGAP expression and its correlation with immune infiltration and clinical data in LUAD patients using multiple datasets, including The Cancer Genome Atlas (TCGA-LUAD), Gene Expression Omnibus (GEO), and scRNA-seq datasets. In vitro and in vivo experiments were conducted to explore the role of TAGAP in CD4+ T cell function, chemotaxis, and cytotoxicity. TAGAP expression was significantly lower in LUAD tissues compared to normal tissues, and high TAGAP expression correlated with better prognosis in LUAD patients. TAGAP was positively correlated with immune/stromal/ESTIMATE scores and immune cell infiltration in LUAD. Single-cell RNA sequencing revealed that TAGAP was primarily distributed in CD4+/CD8+ T cells. In vitro experiments showed that TAGAP overexpression enhanced CD4+ T cell cytotoxicity, proliferation, and chemotaxis. Gene Set Enrichment Analysis (GSEA) indicated that TAGAP was enriched in the JAK-STAT signaling pathway. In vivo experiments in a xenograft tumor model demonstrated that TAGAP overexpression suppressed tumor growth and promoted CD4+ T cell cytotoxicity. TAGAP influences CD4+ T cell differentiation and function in LUAD through the STAT pathway, promoting immune infiltration and cytotoxicity. This study provides a scientific basis for developing novel LUAD immunotherapy strategies and exploring new therapeutic targets.

POLRMT over-expression is linked to WNT/beta-catenin signaling, immune infiltration, and unfavorable outcomes in lung adenocarcinoma patients.

Mitochondrial RNA polymerase (POLRMT) is essential for the expression of mitochondrial genes. In recent studies, POLRMT expression promoted non-small cell cancer cell proliferation in cell lines and xenografts. The present study investigated the impact of POLRMT expression and function on lung adenocarcinoma (LUAD) patients. Multi-omics data (genomics, transcriptomics, and proteomics) from publicly available databases were used to assess the role of POLRMT expression and function in LUAD. These findings were further verified using cancer tissues from clinical samples. POLRMT was over-expressed in LUADs, with mutation frequencies ranging from 1.30% to 5.71%. Over-expression of POLRMT was associated with an abnormal clinicopathological condition resulting in a decreased lifespan. Furthermore, gene sets enrich analysis revealed that POLRMT expression was linked to WNT/beta-catenin signaling; the expression of downstream target genes was positively correlated with POLRMT expression. Also, POLRMT expression was positively correlated with immunosuppressive genes, thereby affecting immune infiltration. POLRMT is over-expressed in LUAD, thereby impacting patient survival. It is also involved in WNT/beta-catenin signaling and may affect tumor infiltration.

PCM1: A Potential Prognostic Biomarker Correlated with Immune Infiltration in Lung Adenocarcinoma

Background: Recent studies have validated the role of Pericentriolar Material 1 (PCM1) in several malignant tumour cell lines, but its specific biological function in lung adenocarcinoma (LUAD) remains unclear. Objective: To address this gap, this study analyzed 411 LUAD and control samples to evaluate the prognostic value of PCM1 using Cox regression analysis. Methods: Multiple genes co-expressed with PCM1 were also analyzed to investigate the biological processes and roles involved in PCM1. An endogenous competitive network with PCM1 as the key gene was constructed to uncover its regulatory and competitive relationships in LUAD. The study further explored the immunological characteristics of PCM1 in different expression groups based on immune infiltration analysis. Results: These findings indicated that higher PCM1 expression levels were associated with better survival prognoses, possibly due to its antagonistic effects on RHOC. Immunological infiltration analysis revealed a significant correlation between PCM1 and various immune cell infiltration levels, including CD4+ T cells, naïve B cells, M2 macrophages, and mast cells. However, there was no significant relationship between PCM1 and MSI, TMB, or stemness, although it was positively correlated with m6A genes. Patients with lower PCM1 expression responded better to CTLA-4 therapy. The study also estimated that some chemotherapeutic and targeted agents might be effective in treating patients with high PCM1 levels. PCM1 was mainly expressed in the cytoplasmic and membranous structures. Conclusion: PCM1 shows potential as a prognostic biomarker for LUAD due to its strong correlation with immune cell infiltration and its ability to enhance anticancer treatment sensitivity.

Tropomyosin 2 exerts anti-tumor effects in lung adenocarcinoma and is a novel prognostic biomarker.

Tropomyosin 2 (TPM2), a member of the actin filament binding protein family, plays distinct roles in the progression of different cancer types. Until now, there has been no study reporting TPM2 expression nor its function in lung adenocarcinoma (LUAD). In the present study, we examined the expression profile of TPM2 by immunohistochemistry (IHC). The clinical significance of TPM2 was assessed by univariate and multivariate analyses. Function of TPM2 in LUAD was evaluated by knockdown and overexpression strategies in three LUAD cell lines, followed by proliferation and invasion assays. Xenografts were conducted in nude mice to further validate the tumor-related role of TPM2. Our results showed that TPM2 was downregulated in LUAD specimens and the low expression of TPM2 was associated with poor outcomes of LUAD patients. Overexpressing TPM2 inhibited cell proliferation and invasion of LUAD cell lines, while silencing TPM2 exerted the opposite effects. The effects of TPM2 in LUAD were further confirmed by xenograft assays. Our results indicated that TPM2 exerted an anti-oncogenic role in LUAD via inhibiting tumor progression, thus providing a novel direction for the prognostic prediction and disease treatment.

Analysis and Validation of the Prognosis ability of the M7GRelated miRNAs in Lung Adenocarcinoma.

N7-methylguanosine (m7G) modification plays a crucial role in the development and progression of lung cancers. MicroRNAs (miRNAs) are closely involved in programmed cell death and the mechanism of tumor growth. The m7G-associated miRNAs genes in lung adenocarcinoma (LUAD), and their prognosis prediction ability of LUAD, however, had not been investigated. The RNA transcriptomes, clinical indices, and immune scores of LUAD patients were searched and downloaded from The Cancer Genome Atlas (TCGA) and the ESTIMATE database. The miRNAs targeting METTL1 and WDR4 were extracted from the TargetScan database. Differentially expressed m7G-related miRNAs were identified and their prediction power of LUAD prognosis was systematically investigated. Among 40 the differentially expressed m7G-related miRNAs in LUAD, five (hsa-miR-31-5p, hsa-miR-5571-3p, hsa-miR-4697-3p, hsa-miR-6858-5p, and hsa-miR-873-3p) demonstrate significant predictive value for prognosis. The risk score constructed by these five miRNAs was an independent prognostic factor (univariate Cox regression results: hazard ratio (HR) = 1.6619, 95% confidential interval (CI) = 1.2103-2.2819, p = 0.0017; multivariate Cox regression results: HR = 1.6004, 95% CI = 1.1633-2.2017, p = 0.0039). The survival curves showed that patients with high-risk scores had a poor prognosis. Calibration curves indicated good predictability in a nomogram constructed combining the miRNA and the clinical indices of age, sex, chemotherapy, radiotherapy, stage, and risk score. GO and KEGG analysis of the overlapping genes showed that the prognostic miRNAs were closely associated with the neuropeptide signaling pathway. Besides, the immune infiltration analysis showed that the expression of the AMPD1 gene was strongly associated with immune cells and immunology functions in LUAD. This study identified DE m7G-related miRNAs and demonstrated their prediction ability in the prognosis of LUAD patients. The risk signature based on these miRNAs demonstrates high accuracy in predicting the prognosis of LUAD patients.

Screening and biomarker assessment of ferroptosis genes FLT3 and ALOX5 in lung adenocarcinoma

Abstract Objectives Ferroptosis is a unique process of cell death that specifically requires iron. We investigated ferroptosis genes and their function in lung adenocarcinoma (LUAD) patients. Methods Data on the expression levels of genes associated with ferroptosis were collected from the FerrDb and the Cancer Genome Atlas database. Kaplan-Meier Plotter was employed to generate the survival curves of LUAD patients with high vs low expression of ferroptosis genes. The relationship between immune cell infiltration and ferroptosis genes was analyzed via TIMMER. Immunohistochemical staining was employed to quantitatively evaluate gene expression in 43 LUAD patients. Results A total of 89 ferroptosis genes were found to have significant differential expression between LUAD and normal tissues (p&lt;0.05), 23 of which were selected and consistent prognostic trends were observed based on analysis of RNA-Seq and RNA microarray data (p&lt;0.05). These 23 ferroptosis genes were assigned to 10 high-abundance pathways and 18 functional categories. Besides, the expression of ALOX5 and FTL3 demonstrated a positive correlation with sets of immune markers. The expression of ALOX5 exhibited a positive correlation with the levels of infiltration of dendritic cells, macrophages, neutrophils, and CD4+ T cells, while FLT3 expression correlated with the infiltration of B cells, CD4+ T cells, neutrophils, and dendritic cells. Furthermore, ALOX5 was confirmed to be downregulated in lung tumor tissues (p&lt;0.01). Conclusions Our findings show that the ferroptosis genes FLT3 and ALOX5 play prominent roles in immune cell infiltration during LUAD progression and may serve as prognostic biomarkers for LUAD.

UHMK1 promotes lung adenocarcinoma oncogenesis by regulating the PI3K/AKT/mTOR signaling pathway.

Effective targeted therapy for lung adenocarcinoma (LUAD), the number one cancer killer worldwide, continues to be a difficult problem because of the limitation of number of applicable patients and acquired resistance. Identifying more promising drug targets for LUAD treatment holds immense clinical significance. Recent studies have revealed that the U2 auxiliary factor (U2AF) homology motif kinase 1 (UHMK1) is a robust pro-oncogenic factor in many cancers. However, its biological functions and the underlying molecular mechanisms in LUAD have not been investigated. The UHMK1 expression in LUAD cells and tissues was evaluated by bioinformatics analysis, immunohistochemistry (IHC), western blotting (WB), and real time quantitative polymerase chain reaction (RT-qPCR) assays. A series of gain- and loss-of-function experiments for UHMK1 were carried out to investigate its biological functions in LUAD in vitro and in vivo. The mechanisms underlying UHMK1's effects in LUAD were analyzed by transcriptome sequencing and WB assays. UHMK1 expression was aberrantly elevated in LUAD tumors and cell lines and positively correlated with tumor size and unfavorable patient prognosis. Functionally, UHMK1 displayed robust pro-oncogenic capacity in LUAD and mechanistically exerted its biological effects via the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. UHMK1 is a potent oncogene in LUAD. Targeting UHMK1 may significantly improve the effect of LUAD treatment via inhibiting multiple biological ways of LUAD progression.

A cuproptosis-related lncRNAs risk model to predict prognosis and guide immunotherapy for lung adenocarcinoma.

Cuproptosis, one of the newest forms of cell death induction, is attracting mounting attention. However, the role of cuproptosis in lung cancer is currently unclear. In this study, we constructed a prognostic signature utilizing cuproptosis-related long noncoding RNAs (CRL) in lung adenocarcinoma (LUAD) and researched its clinical and molecular function. RNA-related and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed CRLs were screened using the 'limma' package of R software. We used coexpression analysis and univariate Cox analysis to further identify prognostic CRLs. Applying least absolute shrinkage and selection operator (LASSO) regression and Cox regression models, a prognostic risk model based on 16 prognostic CRLs was constructed. To validate prognostic CRL function in LUAD, vitro experiments were conducted to explore the expression of GLIS2-AS1, LINC01230, and LINC00592 in LUAD. Subsequently, according to a formula, patients in the training, test, and overall groups were split into high- and low-risk groups. Kaplan-Meier and receiver operating characteristic (ROC) analyses were applied to assess the predictability of the risk model. Finally, the associations between risk signature and immunity-related analysis, somatic mutation, principal component analysis (PCA), enriched molecular pathways, and drug sensitivity was investigated. A cuproptosis-related long noncoding RNAs (lncRNAs) signature was constructed. Using quantitative polymerase chain reaction (qPCR) trial, we verified that the expressions of GLIS2-AS1, LINC01230, and LINC00592 in LUAD cell lines and tissues were consistent with the above screening results. Based on this signature, a total of 471 LUAD samples from TCGA data set were split into two risk groups based on the computed risk score. The risk model showed a better capacity in predicting prognosis than traditional clinicopathological features. Moreover, significant differences were found in immune cell infiltration, drug sensitivity, and immune checkpoint expression between the two risk groups. The CRLs signature was shown to be a prospective biomarker to forecast prognosis in patients with LUAD and presents new insights for personalized treatment of LUAD.

Analysis of Angiogenesis-Related Signatures in the Tumor Immune Microenvironment and Identification of Clinical Prognostic Regulators in Lung Adenocarcinoma.

Tumor angiogenesis is considered to be an important part of the mechanism of tumor progression and metastasis, and its specific function in lung adenocarcinoma has not been fully studied. In this study, we used the transcriptome and genome data of lung adenocarcinoma patients to analyze the expression of 36 angiogenesis regulators in lung adenocarcinoma. Consensus clustering analysis divided lung adenocarcinoma samples into 4 subtypes, A, B, C, and D, and the expression of most angiogenesis regulators in subtype B was higher than that in other subtypes. Immunological analysis indicated that subtype B is likely to display the characteristics of a hot tumor with a more active TME. With the help of Lasso-Cox regression analysis, we successfully constructed a risk model involving five Angiogenesis Regulators genes (CCND2, JAG1, MSX1, STC1, TIMP1), which will be helpful for clinical personalized treatment and prognosis prediction. In addition, JAG1 has the highest mutation rate in tumors, and its cancer-promoting function is reflected in a variety of tumors, which provides important clues for the development of new broad-spectrum anti-cancer targets in the future. We successfully constructed a risk model involving five angiogenesis regulators genes (CCND2, JAG1, MSX1, STC1, TIMP1), which may be helpful for clinical personalized treatment and prognosis prediction. In addition, JAG1 has the highest mutation rate in tumors and plays a leading role in the protein interaction network. Its tumor-promoting function is reflected in a variety of tumors and may become a broad-spectrum anti-cancer target in the future.