Lung Adenocarcinoma Cell Research Articles

Ubiquitin-specific protease 54 regulates GLUT1-mediated aerobic glycolysis to inhibit lung adenocarcinoma progression by modifying p53 degradation.

Lung adenocarcinoma (LUAD) is one of the most prevalent types of cancer. Ubiquitination is crucial in modulating cell proliferation and aerobic glycolysis in cancer. The frequency of TP53 mutations in LUAD is approximately 50%. Currently, therapeutic targets for wild-type (WT) p53-expressing LUAD are limited. In the present study, we systemically explored the expression of ubiquitin-specific protease genes using public datasets. Then, we focused on ubiquitin-specific protease 54 (USP54), and explored its prognostic significance in LUAD patients using public datasets, analyses, and an independent cohort from our center. We found that the expression of USP54 was lower in LUAD tissues compared with that in the paracancerous tissues. Low USP54 expression levels were linked to a malignant phenotype and worse survival in patients with LUAD. The results of functional experiments revealed that up-regulation of USP54 suppressed LUAD cell proliferation in vivo and in vitro. USP54 directly interacted with p53 protein and the levels of ubiquitinated p53 were inversely related to USP54 levels, consistent with a role of USP54 in deubiquitinating p53 in p53-WT LUAD cells. Moreover, up-regulation of the USP54 expression inhibited aerobic glycolysis in LUAD cells. Importantly, we confirmed that USP54 inhibited aerobic glycolysis and the growth of tumor cells by a p53-mediated decrease in glucose transporter 1 (GLUT1) expression in p53-WT LUAD cells. Altogether, we determined a novel mechanism of survival in the p53-WT LUAD cells to endure the malnourished tumor microenvironment and provided insights into the role of USP54 in the adaptation of p53-WT LUAD cells to metabolic stress.

SHP2 mediates STAT3/STAT6 signaling pathway in TAM to inhibit proliferation and metastasis of lung adenocarcinoma.

This study examines SHP2's influence on the STAT3/STAT6 pathway in tumor-associated macrophages (TAMs) and its impact on lung adenocarcinoma proliferation and metastasis. Lung cancer A549 and NCI-H1688 cell lines were subcutaneously injected into nude mice. Macrophages were isolated using flow cytometry and analyzed for CD163, CD206, and Arginase-1 levels via western blot. Similarly, the effect on THP1 cell-associated proteins was assessed. The impact on A549 and NCI-H1688 cell migration, invasion, and proliferation was evaluated through wound healing, Transwell assays, and CCK8. Compared to controls, the sh-RNA SHP2 group showed increased tumor volume and higher expression levels of CD163, CD206, Arginase-1, p-STAT3, p-STAT6, IL-4, IL-10, and various cathepsins in macrophages and THP1 cells. However, p-STAT1 and p-STAT5 levels remained unchanged. The sh-RNA SHP2 group also demonstrated enhanced migration, invasion, and proliferation in both cell lines. SHP2 negatively affects the STAT3/STAT6 pathway in TAMs, promoting M2 polarization and cathepsin secretion, which enhances lung adenocarcinoma cell proliferation and metastasis.

Integrated single-cell and bulk RNA-Seq analysis enhances prognostic accuracy of PD-1/PD-L1 immunotherapy response in lung adenocarcinoma through necroptotic anoikis gene signatures

In addition to presenting significant diagnostic and treatment challenges, lung adenocarcinoma (LUAD) is the most common form of lung cancer. Using scRNA-Seq and bulk RNA-Seq data, we identify three genes referred to as HMR, FAM83A, and KRT6A these genes are related to necroptotic anoikis-related gene expression. Initial validation, conducted on the GSE50081 dataset, demonstrated the model's ability to categorize LUAD patients into high-risk and low-risk groups with significant survival differences. This model was further applied to predict responses to PD-1/PD-L1 blockade therapies, utilizing the IMvigor210 and GSE78220 cohorts, and showed strong correlation with patient outcomes, highlighting its potential in personalized immunotherapy. Further, LUAD cell lines were analyzed using quantitative PCR (qPCR) and Western blot analysis to confirm their expression levels, further corroborating the model's relevance in LUAD pathophysiology. The mutation landscape of these genes was also explored, revealing their broad implication in various cancer types through a pan-cancer analysis. The study also delved into molecular subclustering, revealing distinct expression profiles and associations with different survival outcomes, emphasizing the model’s utility in precision oncology. Moreover, the diversity of immune cell infiltration, analyzed in relation to the necroptotic anoikis signature, suggested significant implications for immune evasion mechanisms in LUAD. While the findings present a promising stride towards personalized LUAD treatment, especially in immunotherapy, limitations such as the retrospective nature of the datasets and the need for larger sample sizes are acknowledged. Prospective clinical trials and further experimental research are essential to validate these findings and enhance the clinical applicability of our prognostic model.

Hypoxia differently regulates the proportion of ALDHhi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/β-catenin pathway.

Cancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self-renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non-small cell lung cancer (NSCLC) remains unclear. The proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit β-catenin while pcDNA3-β-catenin (S33Y) plasmid enhanced the expression of β-catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real-time PCR. We found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, β-catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by β-catenin inhibitor or siRNA knockdown, whereas increased after β-catenin overexpression. Furthermore, hypoxia treatment suppressed E-cadherin expression in H520 cells and enhanced N-cadherin and β-catenin expression, while this effect was completely opposite in A549 cells. The hypoxia-EMT-β-catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.

Polystyrene nanoplastics mediate oxidative stress, senescence, and apoptosis in a human alveolar epithelial cell line

BackgroundNanoplastics, an emerging form of pollution, are easily consumed by organisms and pose a significant threat to biological functions due to their size, expansive surface area, and potent ability to penetrate biological systems. Recent findings indicate an increasing presence of airborne nanoplastics in atmospheric samples, such as polystyrene (PS), raising concerns about potential risks to the human respiratory system.MethodsThis study investigates the impact of 800 nm diameter-PS nanoparticles (PS-NPs) on A549, a human lung adenocarcinoma cell line, examining cell viability, redox balance, senescence, apoptosis, and internalization. We also analyzed the expression of hallmark genes of these processes.ResultsWe demonstrated that PS-NPs of 800 nm in diameter significantly affected cell viability, inducing oxidative stress, cellular senescence, and apoptosis. PS-NPs also penetrated the cytoplasm of A549 cells. These nanoparticles triggered the transcription of genes comprised in the antioxidant network [SOD1 (protein name: superoxide dismutase 1, soluble), SOD2 (protein name: superoxide dismutase 2, mitochondrial), CAT (protein name: catalase), Gpx1 (protein name: glutathione peroxidase 1), and HMOX1 (protein name: heme oxygenase 1)], senescence-associated secretory phenotype [Cdkn1a (protein name: cyclin-dependent kinase inhibitor 1A), IL1A (protein name: interleukin 1 alpha), IL1B (protein name: interleukin 1 beta), IL6 (protein name: interleukin 6), and CXCL8 (protein name: C-X-C motif chemokine ligand 8)], and others involved in the apoptosis modulation [BAX (protein name: Bcl2 associated X, apoptosis regulator), CASP3 (protein name: caspase 3), and BCL2 (protein name: Bcl2, apoptosis regulator)].ConclusionCollectively, this investigation underscores the importance of concentration (dose-dependent effect) and exposure duration as pivotal factors in assessing the toxic effects of PS-NPs on alveolar epithelial cells. Greater attention needs to be directed toward comprehending the risks of cancer development associated with air pollution and the ensuing environmental toxicological impacts on humans and other terrestrial mammals.

PM2.5 regulates the progression of lung adenocarcinoma through the axis of HCG18, miR-195 and ATG14.

Relevant studies have indicated the association of HCG18 with tumour occurrence and progression. In this study, we observed that PM2.5 can enhance the growth of lung adenocarcinoma cells by modulating the expression of HCG18. Further investigations, including overexpression and knockout experiments, elucidated that HCG18 suppresses miR-195, which in turn upregulates the expression of ATG14, resulting in the upregulation of autophagy. Consequently, exposure to PM2.5 leads to elevated HCG18 expression in lung tissues, which in turn increases Atg14 expression and activates autophagy pathways through inhibition of miR-195, thereby contributing to oncogenesis.

KIAA1429 regulates lung adenocarcinoma proliferation and metastasis through the PI3K/AKT pathway by modulating ARHGAP30 expression.

Alterations in epigenetic factors are recognized as key contributors to the emergence of human cancer. The active and reversible alteration of N6-methyladenosine (m6A) RNA is crucial for controlling gene activity and determining cellular destiny. Even with these insights, the triggering of KIAA1429 (also called VIRMA) and its role in lung adenocarcinoma (LUAD) is mostly unclear. As a result, the objective of this study was to elucidate how KIAA1429 contributes to cancer development in LUAD. This study utilized multiple methods for investigation, encompassing the in vitro functional examination of KIAA1429 in lung adenocarcinoma cells, transcriptome sequencing, methylation RNA immunoprecipitation sequencing (MeRIP-seq), as well as RNA stability tests to ascertain the half-life and stability of the target genes. The results indicated that modifying the expression of KIAA1429 regulated the proliferation and metastasis of LUAD. By employing transcriptome sequencing alongside MeRIP-seq analysis, the research pinpointed genes affected by m6A alterations triggered by KIAA1429. In a more detailed manner, it was discovered that KIAA1429 plays a regulatory role in the expression of ARHGAP30. Suppressing KIAA1429 results in reduced m6A levels in the mRNA of the target gene ARHGAP30, boosting its stability and expression, thus inhibiting tumor proliferation and metastasis. This study revealed the activation mechanism and pivotal function of KIAA1429 in LUAD tumor development, paving the way for molecular-based interventions for LUAD.

Expression patterns of HNF4α, TTF-1, and SMARCA4 in lung adenocarcinomas: impacts on clinicopathological and genetic features.

HNF4α expression and SMARCA4 loss were thought to be features of non-terminal respiratory unit (TRU)-type lung adenocarcinomas, but their relationships remained unclear. HNF4α-positive cases among 241 lung adenocarcinomas were stratified based on TTF-1 and SMARCA4 expressions, histological subtypes, and driver mutations. Immunohistochemical analysis was performed using xenograft tumors of lung adenocarcinoma cell lines with high HNF4A expression. HNF4α-positive adenocarcinomas(n = 33) were divided into two groups: the variant group(15 mucinous, 2 enteric, and 1 colloid), where SMARCA4 was retained in all cases, and the conventional non-mucinous group(6 papillary, 5 solid, and 4 acinar), where SMARCA4 was lost in 3/15 cases(20%). All variant cases were negative for TTF-1 and showed wild-type EGFR and frequent KRAS mutations(10/18, 56%). The non-mucinous group was further divided into two groups: TRU-type(n = 7), which was positive for TTF-1 and showed predominantly papillary histology(6/7, 86%) and EGFR mutations(3/7, 43%), and non-TRU-type(n = 8), which was negative for TTF-1, showed frequent loss of SMARCA4(2/8, 25%) and predominantly solid histology(4/8, 50%), and never harbored EGFR mutations. Survival analysis of 230 cases based on histological grading and HNF4α expression revealed that HNF4α-positive poorly differentiated (grade 3) adenocarcinoma showed the worst prognosis. Among 39 cell lines, A549 showed the highest level of HNF4A, immunohistochemically HNF4α expression positive and SMARCA4 lost, and exhibited non-mucinous, high-grade morphology in xenograft tumors. HNF4α-positive non-mucinous adenocarcinomas included TRU-type and non-TRU-type cases; the latter tended to exhibit the high-grade phenotype with frequent loss of SMARCA4, and A549 was a representative cell line.

HMGN1 loss sensitizes lung cancer cells to chemotherapy

The high mobility group nucleosome binding (HMGN) family, constitutes a large family of non-histone protein family known to bind the acidic patch of the nucleosomes with various key cellular functions. Several studies have highlighted the pivotal roles of HMGNs in the pathogenic process of various cancer types. However, the roles of HMGN family in lung adenocarcinoma (LUAD) have not been fully elucidated. Herein, integrative analyses of multiple-omics data revealed that HMGNs frequently exhibit dysregulation in LUAD. Subsequent analysis of the clinical relevance of HMGN1 demonstrated its association with poor prognosis in LUAD and its potential as a diagnostic marker to differentiate LUAD from healthy controls. Additionally, functional enrichment analysis suggested that HMGN1 was mainly involved in DNA repair. To corroborate these findings, cellular experiments were conducted, confirming HMGN1’s crucial involvement in homologous recombination repair and its potential to enhance the sensitivity of LUAD cells to standard chemotherapeutic drugs. This study proposes HMGN1 as a novel prognostic biomarker and a promising target for chemotherapy in lung adenocarcinoma.

Influence of TLR4 signaling on Cannabidiol’s antitumor effectiveness in lung adenocarcinoma cells

Abstract Objectives Lung cancer remains a predominant cancer type with high incidence and low survival rates. Key challenges in its treatment include impaired cellular mechanisms, notably resistance to apoptosis and altered immune responses. A critical aspect in this context is the heightened TLR4-mediated signaling, known to promote cell survival, metastasis, and resistance to cell death, particularly impacting immune microenvironment regulation. This study focuses on evaluating the impact of TLR4 signaling activation on potential therapeutic strategies. Methods Our research utilizes Cannabidiol (CBD), a compound already employed in mitigating chemotherapy side effects in lung adenocarcinoma, recognized for its antitumor properties including antiproliferative, antimetastatic, and apoptosis-inducing effects. However, the effectiveness of CBD in lung cancer cells with elevated TLR4 signaling remains uncertain. Results Our findings reveal that the combination of CBD and TLR4 agonist affects cell viability, proliferation, cell cycle progression, apoptosis, and gene expression related to immune response and extracellular matrix regulation. In lung adenocarcinoma cells with activated TLR4, CBD shows an increased IC50 value, reflecting reduced antiproliferative capacity. Furthermore, its efficacy in arresting the cell cycle and inducing apoptosis is also compromised. The influence on immune response and extracellular matrix regulation is also altered in TLR4-activated cells. Conclusions These results indicate that TLR4 activation significantly diminishes the antitumor efficacy of CBD. This highlights the importance of considering TLR4 signaling activation in future research on therapeutic agents like CBD for cancer treatment.

N-Hydroxyalkanamide Based Organo/hydrogels as Novel Scaffolds for pH-Dependent Metronidazole and Theophylline Release.

The traditional delivery of metronidazole and theophylline presents challenges like bitter taste, variable absorption, and side effects. However, gel-based systems offer advantages including enhanced targeted drug delivery, minimized side effects, and improved patient compliance, effectively addressing these challenges. Consequently, a cost-effective synthesis of N-hydroxyalkanamide gelators with varying alkyl chain lengths was achieved in a single-step reaction procedure. These gelators formed self-assembled aggregates in DMSO/water solvent system, resulting in organo/hydrogels at a minimum gelation concentration of 1.5% w/v. Subsequently, metronidazole and theophylline were encapsulated within the gel core and released through gel-to-sol transition triggered by pH variation at 37 °C, while maintaining the structural-activity relationship. UV-vis spectroscopy was employed to observe the drug release behavior. Furthermore, in vitro cytotoxicity assays revealed cytotoxic effects against A549 lung adenocarcinoma cells, indicating anti-proliferative activity against human lung cancer cells. Specifically, the gel containing theophylline (16HAD+Th) exhibited cytotoxicity on cancerous A549 cells with IC50 values of 19.23 ± 0.6 µg/mL, followed by the gel containing metronidazole (16HAD+Mz) with IC50 values of 23.75 ± 0.7 µg/mL. Moreover, the system demonstrated comparable antibacterial activity against both gram-negative (E. coli) and gram-positive bacteria (S. aureus).

Smoking-induced CCNA2 expression promotes lung adenocarcinoma tumorigenesis by boosting AT2/AT2-like cell differentiation

Lung adenocarcinoma (LUAD), a type of non-small cell lung cancer (NSCLC), originates from not only bronchial epithelial cells but also alveolar type 2 (AT2) cells, which could differentiate into AT2-like cells. AT2-like cells function as cancer stem cells (CSCs) of LUAD tumorigenesis to give rise to adenocarcinoma. However, the mechanism underlying AT2 cell differentiation into AT2-like cells in LUAD remains unknown. We analyze genes differentially expressed and genes with significantly different survival curves in LUAD, and the combination of these two analyses yields 147 differential genes, in which 14 differentially expressed genes were enriched in cell cycle pathway. We next analyze the protein levels of these genes in LUAD and find that Cyclin-A2 (CCNA2) is closely associated with LUAD tumorigenesis. Unexpectedly, high CCNA2 expression in LUAD is restrictedly associated with smoking and independent of other driver mutations. Single-cell sequencing analyses reveal that CCNA2 is predominantly involved in AT2-like cell differentiation, while inhibition of CCNA2 significantly reverses smoking-induced AT2-like cell differentiation. Mechanistically, CCNA2 binding to CDK2 phosphorylates the AXIN1 complex, which in turn induces ubiquitination-dependent degradation of β-catenin and inhibits the WNT signaling pathway, thereby failing AT2 cell maintenance. These results uncover smoking-induced CCNA2 overexpression and subsequent WNT/β-catenin signaling inactivation as a hitherto uncharacterized mechanism controlling AT2 cell differentiation and LUAD tumorigenesis.

Knockdown of NADK promotes LUAD ferroptosis via NADPH/FSP1 axis

BackgroundLung cancer is a serious threat to human health and is the first leading cause of cancer death. Ferroptosis, a newly discovered form of programmed cell death associated with redox homeostasis, is of particular interest in the lung cancer, given the high oxygen environment of lung cancer. NADPH has reducing properties and therefore holds the potential to resist ferroptosis. Resistance to ferroptosis exists in lung cancer, but the role of NADK in regulating ferroptosis in lung cancer has not been reported yet.MethodsImmunohistochemistry (IHC) was used to analyse the expression of NADK in 86 cases of lung adenocarcinoma(LUAD) and adjacent tissues, and a IHC score was assigned to each sample. Chi-square and kaplan-meier curve was performed to analyse the differences in metastasis and five-year survival between the two groups with NADK high or low scores. Proliferation of NADK-knockdown LUAD cell lines was detected in vivo and vitro. Furthermore, leves of ROS, MDA and Fe2+ were measured to validate the effect and mechanism of NADK on ferroptosis in LUAD.ResultsThe expression of NADK was significantly evaluated in LUAD tissues as compared to adjacent non-cancerous tissues. The proliferation of NADK-knockdown cells was inhibited both in vivo and vitro, and increasing levels of intracellular ROS, Fe2+ and lipid peroxide products (MDA) were observed. Furthermore, NADK-knockdown promoted the ferroptosis of LUAD cells induced by Erastin/RSL3 by regulating the level of NADPH and the expression of FSP1. Knockdown of NADK enhanced the sensitivities of LUAD cells to Erastin/RSL3-induced ferroptosis by regulating NADPH level and FSP1 expression.ConclusionsNADK is over-expressed in LUAD patients. Knockdown of NADK inhibited the proliferation of LUAD cells both in vitro and in vivo and promotes the Erastin/RSL3-induced ferroptosis of LUAD cells by down-regulating the NADPH/FSP1 axis.

LINC01572 promotes the malignant progression of lung adenocarcinoma by modulating p53 mediated by miRNA-338-5p/TTK axis.

Lung cancer is one of the malignant tumors that threaten human health seriously. Long non-coding RNA (lncRNA) is an important factor affecting tumorigenesis and development. However, the mechanism of lncRNA in lung cancer progression remains to be further explored. In this study, the TCGA database was analyzed, and LINC01572 was found to be increased in lung adenocarcinoma (LUAD) tissues. Thereafter, with the help of databases including lncBase, TargetScan, and mirDIP, as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, LINC01572/miRNA-338-5p/TTK regulatory axis and downstream p53 signaling pathway were excavated. qRT-PCR was adopted to detect levels of LINC01572, miRNA-338-5p, and TTK in LUAD cells. The role that LINC01572 played in LUAD cells was validated by CCK-8 assay, flow cytometry, colony formation, Transwell, and scratch healing assays. The binding ability between LINC01572/TTK and miRNA-338-5p was then verified by dual-luciferase and RIP analysis. The results of this study demonstrated that LINC01572 was elevated in LUAD cells compared with normal cells. The overexpression of LINC01572 promoted the proliferative and migratory properties of LUAD cells but inhibited cell apoptosis. The inhibition of LINC01572 resulted in the opposite result. In addition, rescue experiments revealed that LINC01572, as a molecular sponge of miRNA-338-5p, targeted TTK to manipulate p53 for facilitating LUAD cell malignant progression. Apart from this, we constructed a mouse xenograft model and confirmed that the knockdown of LINC01572 hindered the growth of LUAD solid tumors in vivo. Our findings illuminated the molecular mechanism of LINC01572 influencing LUAD and provided new insights for targeted therapy of LUAD cells.

SMC2 knockdown inhibits malignant progression of lung adenocarcinoma by upregulating BTG2 expression

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer worldwide. Structural maintenance of chromosomes 2 (SMC2) serves as a predictor of poor prognosis across various cancer types. This study aims to explore the role and underlying mechanisms of SMC2 in LUAD progression. The expression of SMC2 in LUAD tissues and its correlation with prognosis were analyzed by public databases. Knockdown of SMC2 was performed to assess the proliferation, migration and invasion ability of LUAD cells. Bulk RNA sequencing analysis identified enriched cellular pathways and remarkable upregulation of BTG anti-proliferation factor 2 (BTG2) expression after SMC2 knockdown in LUAD cells. Then, BTG2 was silenced to assess the malignant behavior of LUAD cells. Subcutaneous transplantation and intracranial models of LUAD cells in BALB/c nude mice were established to assess the antineoplastic effect of SMC2 knockdown in vivo. Additionally, a lung metastasis model was created to evaluate the pro-metastatic effect of SMC2. Our findings indicated that SMC2 was upregulated in LUAD tissues and cell lines, with higher expression correlating with poor prognosis. SMC2 silencing suppressed the proliferation, migration and invasion ability of LUAD cells by upregulating BTG2 expression via p53 and inactivating ERK and AKT pathways. BTG2 silencing reversed the effects of SMC2 downregulation on malignant behaviors of LUAD cells and restored the phosphorylated ERK and AKT levels. Furthermore, SMC2 knockdown effectively prevented the formation of subcutaneous, intracranial and metastatic tumor in vivo, and upregulation of BTG2 expression after SMC2 knockdown was confirmed in tumor models. This study revealed that SMC2 knockdown restrained the malignant progression of LUAD through upregulation of BTG2 expression and inactivation of ERK and AKT pathway, and SMC2 could be a potential therapeutic target for LUAD treatment.

Identifying lncRNAs and mRNAs related to survival of NSCLC based on bioinformatic analysis and machine learning.

Non-small cell lung cancer (NSCLC) is the most common histopathological type, and it is purposeful for screening potential prognostic biomarkers for NSCLC. This study aims to identify the lncRNAs and mRNAs related to survival of non-small cell lung cancer (NSCLC). The expression profile data of lung adenocarcinoma and lung squamous cell carcinoma were downloaded in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset. A total of eight survival related long non-coding RNAs (lncRNAs) and 262 survival related mRNAs were filtered. By gene set enrichment analysis, 17 significantly correlated Gene Ontology signal pathways and 14 Kyoto Encyclopedia of Genes and Genomes signal pathways were screened. Based on the clinical survival and prognosis information of the samples, we screened eight lncRNAs and 193 mRNAs by single factor Cox regression analysis. Further single and multifactor Cox regression analysis were performed, 30 independent prognostication-related mRNAs were obtained. The PPI network was further constructed. We then performed the machine learning algorithms (Least absolute shrinkage and selection operator, Recursive feature elimination, and Random forest) to screen the optimized DEGs combination, and a total of 17 overlapping mRNAs were obtained. Based on the 17 characteristic mRNAs obtained, we firstly built a Nomogram prediction model, and the ROC values of training set and testing set were 0.835 and 0.767, respectively. By overlapping the 17 characteristic mRNAs and PPI network hub genes, three genes were obtained: CDC6, CEP55, TYMS, which were considered as key factors associated with survival of NSCLC. The in vitro experiments were performed to examine the effect of CDC6, CEP55, and TYMS on NSCLC cells. Finally, the lncRNAs-mRNAs networks were constructed.

Abnormal methylation mediated upregulation of LINC00857 boosts malignant progression of lung adenocarcinoma by modulating the miR‐486‐5p/NEK2 axis

AbstractLINC00857 is frequently dysregulated in varying cancers, which in turn exerts carcinogenic effects; however, its DNA methylation status in promoter region and molecular mechanisms underlying the progression of lung adenocarcinoma (LUAD) remain rarely understood. Through bioinformatics analysis, we examined the expression state and methylation site of LINC00857 in LUAD and further investigated the properties of LINC00857 as a competitive endogenous RNA in the cancer progression. The current study revealed that the overexpression of LINC00857 in LUAD tissue and cells was mainly caused by the hypomethylation of the promoter region. LINC00857 knockdown prominently reduced cell proliferation, impeded cell migration and invasion, and restrained lymph node metastasis, with enhancing radiosensitivity. The effects of LINC00857 on tumor growth were also investigated in nude mice models. Subsequently, the downstream factors, miR‐486‐5p and NEK2, were screened, and the putative regulatory axis was examined. Overall, the regulatory effect of methylation‐mediated LINC00857 overexpression on miR‐486‐5p/NEK2 axis may be a new mechanism for LUAD progression.

Unique aminothiazolyl coumarins as potential DNA and membrane disruptors towards Enterococcus faecalis

Aminothiazolyl coumarins as potentially new antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. Biological activity assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens. Especially, aminothiazolyl 7-propyl coumarin 8b and 4-dichlorobenzyl derivative 11b exhibited bactericidal potential (MBC/MIC = 2) toward clinically drug-resistant Enterococcus faecalis with low cytotoxicity to human lung adenocarcinoma A549 cells, rapidly bactericidal effects and no obvious bacterial resistance development against E. faecalis. The preliminary antibacterial action mechanism studies suggested that compound 11b was able to disturb E. faecalis membrane effectively, and interact with bacterial DNA isolated from resistant E. faecalis through noncovalent bonds to cleave DNA, thus inhibiting the growth of E. faecalis strain. Further molecular modeling indicated that compounds 8b and 11b could bind with SER-1084 and ASP-1083 residues of gyrase-DNA complex through hydrogen bonds and hydrophobic interactions. Moreover, compound 11b showed low hemolysis and in vivo toxicity. These findings of aminothiazolyl coumarins as unique structural scaffolds might hold a large promise for the treatments of drug-resistant bacterial infection.

SYSTEMATIC SCREENING OF SYNTHETIC ORGANOCHALCOGEN COMPOUNDS WITH ANTICANCER ACTIVITY USING HUMAN LUNG ADENOCARCINOMA SPHEROIDS

Lung adenocarcinoma stands as a leading global cause of cancer-related fatalities, with current therapeutic approaches remaining unsatisfactory. Given the association between elevated oxidative markers and the aggressive nature of cancer cells (including multidrug resistance and metastatic potential) that can predict poor outcome of lung adenocarcinoma patients, any compounds that interfere with their aberrant redox biology should be rationally explored as innovative intervention strategies. This study was designed to screen potential anticancer activities within nine newly synthesized organochalcogen - compounds characterized by the presence of oxygen, sulfur, or selenium elements in their structure and exhibiting antioxidant activity - and systematically evaluated their performance against cisplatin, the cornerstone therapeutic agent for lung adenocarcinoma. Our methodology involved the establishment of optimal conditions for generating single tumor spheroids using A549 human lung adenocarcinoma cell line. The initiation interval for spheroid formation was determined to be four days in vitro (DIV), and these single spheroids demonstrated sustained growth over a period of 20 DIV. Toxic dose-response curves were subsequently performed for each compound after 24 and 48 hours of incubation at the 12nd DIV. Our findings reveal that at least two of the synthetic organochalcogen compounds exhibited noteworthy anticancer activity, surpassing cisplatin in key parameters such as lower LD (Lethal Dose) 50, larger drug activity area, and maximum amplitude of effect, and are promising drugs for futures studies in the treatment of lung adenocarcinomas. Physicochemical descriptors and prediction ADME (absorption, distribution, metabolism, and excretion) parameters of selected compounds were obtained using SwissADME computational tool; Molinspiration server was used to calculate a biological activity score, and possible molecule targets were evaluated by prediction with the SwissTargetPrediction server. This research not only sheds light on novel avenues for therapeutic exploration but also underscores the potential of synthetic organochalcogen compounds as agents with superior efficacy compared to established treatments.

Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients

BackgroundThe excessive accumulation of lactate within the tumor microenvironment (TME) has been demonstrated to facilitate tumor advancement and evade the immune system. Nonetheless, the metabolic status of lactate in lung adenocarcinoma (LUAD) remains uncertain. MethodBy analyzing the transcriptome profile of patients with LUAD, we created a lactate metabolism score (LMS) to predict survival. We then conducted a comprehensive examination of the biological functions and immune infiltration among different LMS patient groups. Moreover, we assessed the LMS predictive efficacy in chemotherapy and immunotherapy. Finally, we validated the detrimental phenotypic effects of SLC16A3 on LUAD cell lines (PC9 and A549) through in vitro experiments. We collected clinical samples to assess the prognostic impact of SLC16A3. ResultsWe constructed an LMS model with 6 lactate metabolism regulatory factors using LASSO regression. The high LMS model indicates worse clinical outcomes for LUAD patients. High LMS patients are associated with metabolic dysregulation and increased infiltration of M0 and M1 macrophages. Low LMS patients are related to upregulated citric acid metabolism pathways and memory immune cells. High LMS patients are suitable for traditional chemotherapy, while patients with low LMS are more likely to benefit from immunotherapy. Lastly, downregulating SLC16A3 significantly reduces the proliferative and invasive capabilities of LUAD cell lines. Clinical cohort shows that patients with high expression of SLC16A3 have a worse prognosis. ConclusionsThe LMS model constructed based on the lactate metabolism pathway displays high effectiveness in predicting the outcome of patients with LUAD. LMS can offer direction regarding chemotherapy as well as immunotherapy in LUAD.