Solid tumors create an acidic tumor microenvironment (TME) that drives cancer progression, therapy resistance, and immune evasion. Bicarbonate is crucial for maintaining acid-base balance, however, its role in non-small cell lung cancer (NSCLC) remains unclear. Through the analysis of single-cell RNA sequencing data and the TCGA and CPTAC databases, we identified solute carrier family 4 member 7 (SLC4A7) as the predominantly expressed bicarbonate transporter in NSCLC. Functionally, SLC4A7 knockdown impaired bicarbonate uptake, resulting in intracellular acidification and extracellular alkalinization. This phenomenon led to a decrease in glycolysis and subsequently suppressed the growth and metastasis of NSCLC. Both in vivo and in vitro data demonstrate that the alkalinization of the TME induced by Slc4a7 knockout enhances the infiltration and function of cytotoxic T cells, significantly inhibiting tumor growth. Additionally, Slc4a7 knockout exhibits synergistic antitumor efficacy in combination with PD-1/PD-L1 immune checkpoint inhibitors. Mechanistically, integrative analysis of RNA-seq and ATAC-seq data identified CTCF as a transcription factor regulating SLC4A7 expression. In summary, our study demonstrates that SLC4A7-mediated bicarbonate transport is crucial for maintaining acid-base homeostasis in NSCLC and represents a promising therapeutic target for this disease.

Histological transformation represents an important mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant lung cancer; however, its incidence, timing, and post-transformation outcomes remain incompletely characterized. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines and Cochrane recommendations. PubMed, Web of Science and Embase were searched up to November 2025 for studies reporting histological transformation in EGFR-mutant lung cancer following EGFR-TKI resistance. Eligible studies included prospective or retrospective studies and consecutive case series (sample size ≥ 10 or ≥3events). Random-effects models were applied to pool transformation proportions and survival outcomes, and Kaplan–Meier–based methods were used to synthesize time-to-event data. A total of 35 studies were included. Among patients with non–small cell lung cancer (NSCLC) who developed resistance to EGFR-TKIs, the pooled proportion of transformation to high-grade neuroendocrine carcinoma (HGNEC) was 6

Background: CCL20 is a key chemokine involved in tumor-associated inflammation and immune microenvironment remodeling, but its biological and clinical relevance in esophageal cancer (ESCA) and across cancers remains incompletely defined. This study aimed to systematically characterize the expression pattern, prognostic value, immune associations, and potential translational relevance of CCL20 using an integrative multi-omics framework. Methods: The biological and clinical significance of CCL20 was investigated through differential expression analysis, weighted gene co-expression network analysis, survival and clinicopathological association analyses, ROC-based diagnostic evaluation, immune infiltration and tumor microenvironment characterization, immune checkpoint correlation analysis, single-cell transcriptomic analysis, in silico knockout analysis, drug sensitivity prediction, molecular docking, and tissue microarray-based immunohistochemistry. Results: CCL20 was aberrantly upregulated in ESCA and multiple other solid tumors, and its high expression was associated with poor prognosis in several cancer types. Tissue microarray-based immunohistochemistry further confirmed CCL20 overexpression at the protein level in ESCA. In the TCGA cohort, CCL20 showed favorable diagnostic performance and was associated with poorer survival outcomes in ESCA. High CCL20 expression was also closely associated with immunoregulatory infiltration patterns, increased immune checkpoint expression, and enhanced stromal features. Single-cell analysis showed that CCL20 was predominantly expressed in monocytes/macrophages and may mediate immune communication between myeloid and lymphoid/dendritic cells through the CCL20-CCR6 axis. In silico knockout analysis further suggested that CCL20 depletion perturbs inflammation-, chemotaxis-, and immune regulation-related transcriptional programs in monocytes/macrophages. Drug sensitivity prediction and molecular docking provided preliminary clues supporting the therapeutic relevance of the CCL20 axis. Conclusions: CCL20 may represent a biologically relevant candidate biomarker in ESCA, with potential diagnostic, prognostic, and therapeutic relevance.

Bronchus and lung cancer are one of the most common and deadly types of cancer in the United States. This study analyzed the mortality trends related to bronchus and lung cancer among U.S. adults ≥ 25 years old from 1999 to 2023 from demographic and geographic perspectives. We utilized the CDC WONDER database to investigate the trends in Bronchus and lung cancer-related mortality in the United States. Age-adjusted mortality rates per 100,000 people (AAMR), annual percentage change (APC), and average annual percentage change (AAPC) with 95

Background: Chronic obstructive pulmonary disease (COPD) is the most common respiratory disease among middle-aged and older adults worldwide, and its etiology remains incompletely understood. As intermediate products of biochemical reactions, blood metabolites have a debated role in the pathogenesis of COPD, with observational studies yielding conflicting results. Most existing genetic studies are based on European cohorts, whereas East Asian populations differ substantially in genetic architecture and environmental exposures, limiting the generalizability of current findings. Methods: We performed two-sample Mendelian randomization (MR) leveraging the most recently released summary statistics from large-scale genome-wide association studies (GWAS) in East Asian populations. Independent SNPs significantly associated with circulating metabolite levels were selected from multiple East Asian datasets as instrumental variables (3432 Chinese participants, 2022). Outcome data were obtained from two independent East Asian COPD GWAS cohorts: ebi-a-GCST90018587 (4017 cases, 162,653 controls, BioBank Japan, 2021) and bbj-a-103 (3315 cases, 201,592 controls, BioBank Japan, 2019). Inverse-variance weighting (IVW) served as the primary estimator, with sensitivity analyses conducted using MR-Egger regression, the weighted median, and additional complementary approaches. Results: Seven blood metabolites showed suggestive causal links with COPD. In the ebi-a-GCST90018587 cohort, genetically predicted platelet count was positively associated with COPD risk (OR = 1.51, 95% CI 1.01- 2.27, P = 0.0467), and in the bbj-a-103 cohort higher genetically predicted manganese levels likewise indicated increased risk (OR = 1.27, 95% CI 1.00- 1.62, P = 0.0460). Conversely, higher genetically predicted levels of leucine (OR = 0.56, 95% CI 0.34- 0.91, P = 0.0197), alpha-aminoadipic acid (OR = 0.75, 95% CI 0.59- 0.96, P = 0.0208), serum-alanine-transaminase (ALT)(OR = 0.87, 95% CI 0.76- 0.99, P = 0.0345), phosphoethanolamine (OR=0.75, 95% CI 0.56- 1.00, P = 0.0500), and 25-hydroxyvitamin-D2 (OR = 0.81, 95% CI 0.70- 0.94, P = 0.0045) were associated with lower COPD risk, with phosphoethanolamine and 25-hydroxyvitamin-D2 showing concordant directions and comparable effect sizes across the two independent COPD GWAS cohorts. For all exposures, Cochran's Q tests and MR-Egger intercepts indicated no significant heterogeneity (P > 0.05), and Steiger directionality tests (P< 0.05) did not suggest reverse causation. Conclusion: Leveraging large East Asian cohorts, this study provides MR evidence implicating amino-acid metabolism, phospholipid metabolism, vitamin D status, and selected trace elements in COPD pathophysiology. The replicated protective signals for phosphoethanolamine and 25(OH)D-2, and the risk signals for platelet count and manganese, offer East Asian-specific genetic support for metabolically oriented prevention and precision interventions.

BACKGROUND:Observational studies have revealed that the levels of unsaturated fatty acids (UFAs) may influence the development, progression, and management of chronic obstructive pulmonary disease (COPD). To investigate the association between UFAs and COPD, we performed a bidirectional Mendelian randomization (MR) study. METHODS:We extracted summary genome-wide association statistics (GWAS) for UFAs (N = 115 082) among population from UK Biobank study by measuring circulating lipoprotein lipid concentrations. The genetic instrument for COPD was derived from the FinnGen, which included 338 303 COPD controls and 20 066 cases of the disease. Measured at the genome-wide significance level, independent genetic variations associated with each characteristic were considered instrumental factors. Two-sample MR analysis was mainly conducted utilizing the inverse-variance-weighted (IVW) approach, complemented by the weighted median method and the MR-Egger regression. RESULTS:IVW MR analysis significantly demonstrated that the level of docosahexaenoic acid (DHA) (OR 0.812, 95% CI 0.719-0.918, p < 0.001), linoleic acid (LA) (OR 0.850, 95% CI 0.781-0.926, p < 0.001), the levels of omega-3 fatty acids (OR 0.884, 95% CI 0.781-0.99, p = 0.049), omega-6 fatty acids (OR 0.878, 95% CI 0.812-0.950, p = 0.001), and polyunsaturated fatty acids (PUFAs) (OR 0.901, 95% CI 0.827-0.982, p = 0.018) all linked to a higher risk of COPD. Moreover, in reverse direction MR analysis, genetic liability to COPD showed associations with higher levels of monounsaturated fatty acids (MUFAs) (OR 1.040, 95% CI 1.010-1.071, p = 0.008). Horizontal pleiotropy is not likely to materially skew the causative estimates from sensitivity analysis. CONCLUSION:Our research added credence to the current evidence that suggests a bidirectional causal link between UFAs and COPD. It is imperative to comprehend this connection in order to effectively prevent and manage COPD.

Surgery remains the main curative treatment for lung cancer patients. However, operation has resulted in some-degree reduction in postoperative pulmonary function. The decreased pulmonary function could be rehabilitated to the preoperative level through restoring exercise, which is related to the ways and exercise time of rehabilitating. The Dignio platform is 1 digital telemedicine system and has been used maturely in Norway, however, it has not yet been widely promoted in China. In the present study, we adopted the telemedicine system, according to the formulated rehabilitation exercise program, to design a good way to recover pulmonary function for postoperative lung cancer patients, promoting early and quick recovery, and reducing the long-term postoperative complications and outpatient visits. This retrospective controlled study enrolled 250 postoperative lung cancer patients using a remote digital care platform and 250 matched controls receiving standard instructions. In the postoperative 1-week follow-up, we found that the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory volume in 6 seconds, FVC25-75, peak expiratory flow had an obvious upward trend, although there were no significant differences in the measurements on postoperative day 7 compared with day 1. From the long-term data at 1 month/3 months/6 months post-operation, we found that the recovery was better to varying degrees in the experiment group using the remote care digital platform, compared with that of the control, especially the FEV1 at 3 (P = .065) and 6 months post-operation (P = .037), and forced Expiratory Flow between 25% and 75% of forced vital capacity at 3 months post-operation (P = .084). However, most pulmonary values, such as the FEV1/FVC, FVC and peak expiratory flow have no significant difference (all P > .05) in the recovery at 1 month post-operation between the experimental group and control, the second time at 3 months and the third time at 6 months after surgery. Especially in the experimental group, 2 patients with sudden pneumothorax were timely detected after discharge through the Digino platform, the patient returned to the hospital in time, and both patients were out of danger ultimately. The Digino remote care indeed has some benefit in the pulmonary function recovery in the long-term follow up, and reduces postoperative complications obviously.

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9–13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3, MYC, SOX2, and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

Glucose deprivation is a prevalent stressor within the tumor microenvironment. Nonetheless, the fundamental mechanism through which non-small cell lung cancer (NSCLC) cells orchestrate survival and progression through specific metabolic hubs under such conditions remains poorly understood. This study utilized integrated multiomics analyses, encompassing transcriptomics and metabolomics, to identify pivotal targets. Functional validation was performed via in vitro assays, including CCK-8, colony formation, Transwell, and EdU assays, as well as in vivo models, such as subcutaneous xenografts and tail-vein lung metastasis models. The function and mechanism of the MAPK/ATF3/ASNS signaling axis were comprehensively investigated using gene knockdown/overexpression techniques, Western blotting, immunohistochemistry, and metabolomic analysis. Combined transcriptomic and metabolomic analyses revealed that glucose deprivation markedly upregulates ASNS expression in NSCLC cells, correlating with unfavorable patient outcomes. Functionally, both in vitro and in vivo experiments confirmed that ASNS significantly promotes the malignant behaviors of NSCLC cells under glucose-deprived conditions. Metabolomic analysis revealed that ASNS supports tumor cell survival during energetic stress by maintaining a dynamic balance of multiple amino acids. Mechanistically, glucose deprivation activates the MAPK signaling pathway, leading to the upregulation of the transcription factor ATF3, which binds directly to the ASNS promoter and transcriptionally activates its expression, thereby promoting malignant progression in NSCLC. Finally, the combined targeting of glucose metabolism using 2-DG, along with ASNS inhibition, demonstrated additive antitumor efficacy in vivo. The results of this study revealed that, under glucose deprivation stress, the MAPK/ATF3/ASNS axis functions as a critical signaling–metabolic hub, promoting NSCLC progression by driving amino acid metabolic reprogramming. Targeting this axis offers a novel strategy for intervening in tumor metabolic adaptation and developing innovative combination therapies.

OBJECTIVE:To investigate the role and mechanism of SERPINE1 in gefitinib (GEF) resistance in lung cancer and to identify a novel therapeutic target for overcoming chemoresistance. METHODS:GEF-resistant (GR) cell lines PC-9/GR and HCC827/GR were established. Cell viability, proliferation, death, migration, and invasion were assessed using CCK-8, colony formation, Calcein-AM/PI staining, and Transwell assays. Gene and protein expression were determined by RT-qPCR and Western blot. Transcriptional regulation was verified via ChIP-qPCR and dual-luciferase reporter assays, respectively. Protein-protein interactions were screened via co-immunoprecipitation and LC-MS/MS. The molecular mechanism was further elucidated using ubiquitination and protein stability assays. Ferroptosis-related indicators were evaluated by measuring intracellular Fe2+, lipid peroxidation, malondialdehyde, and immunohistochemistry. A mouse xenograft model was established to validate the findings in vivo. RESULTS:SERPINE1 expression was elevated in GR lung cancer cells and correlated with poor patient prognosis. SERPINE1 knockdown reduced the half-maximal inhibitory concentration of GEF in resistant cells, while also inhibiting cellular proliferation, migration, and invasion, and promoting cell death. ELK3 was identified as an upstream transcription factor promoting SERPINE1 transcriptional activity. Furthermore, ELK3-mediated GEF resistance was dependent on SERPINE1. SERPINE1 maintained PCBP2 protein stability by inhibiting its ubiquitination and subsequent lysosomal degradation. PCBP2 overexpression suppressed ferroptosis and enhanced GEF resistance. In vivo experiments demonstrated that knockdown of SERPINE1 inhibited tumor growth and enhanced the antitumor efficacy of GEF, whereas overexpression of PCBP2 reversed this effect. CONCLUSION:The ELK3-SERPINE1-PCBP2 axis promotes GEF resistance in lung cancer by inhibiting ferroptosis, providing a potential new therapeutic strategy for overcoming chemoresistance.

ANZ Journal of SurgeryEarly View LETTER TO THE EDITOR Giant lower thoracic oesophageal lipoma Yang Fuzhi MSc, Yang Fuzhi MSc Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Shanghai Key Laboratory of Clinical Geriatric Medicine, HuaDong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Data curation, Methodology, Writing - original draftSearch for more papers by this authorZhu Xunxia MSc, Zhu Xunxia MSc Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Writing - review & editingSearch for more papers by this authorChen Xiaoyu PhD, Chen Xiaoyu PhD Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Visualization, Writing - original draftSearch for more papers by this authorZhang Xuelin MSc, Zhang Xuelin MSc Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Conceptualization, Project administration, SupervisionSearch for more papers by this authorShen Xiaoyong PhD, Shen Xiaoyong PhD [email protected] orcid.org/0000-0001-5922-2589 Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Conceptualization, Project administration, SupervisionSearch for more papers by this author Yang Fuzhi MSc, Yang Fuzhi MSc Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Shanghai Key Laboratory of Clinical Geriatric Medicine, HuaDong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Data curation, Methodology, Writing - original draftSearch for more papers by this authorZhu Xunxia MSc, Zhu Xunxia MSc Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Writing - review & editingSearch for more papers by this authorChen Xiaoyu PhD, Chen Xiaoyu PhD Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Visualization, Writing - original draftSearch for more papers by this authorZhang Xuelin MSc, Zhang Xuelin MSc Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Conceptualization, Project administration, SupervisionSearch for more papers by this authorShen Xiaoyong PhD, Shen Xiaoyong PhD [email protected] orcid.org/0000-0001-5922-2589 Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China Contribution: Conceptualization, Project administration, SupervisionSearch for more papers by this author First published: 25 April 2024 https://doi.org/10.1111/ans.19013Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Caceres M, Steeb G, Wilks SM, Garrett HE Jr. Large pedunculated polyps originating in the esophagus and hypopharynx. Ann. Thorac. Surg. 2006; 81: 393–396. 10.1016/j.athoracsur.2005.05.106 PubMedWeb of Science®Google Scholar 2Pallabazzer G, Santi S, Biagio S, D'Imporzano S. Difficult polypectomy-giant hypopharyngeal polyp: case report and literature review. World J. Gastroenterol. 2013; 19: 5936–5939. 10.3748/wjg.v19.i35.5936 PubMedWeb of Science®Google Scholar 3Zhao X, Wang X, Li A, Sheng J. Endoscopic resection of a giant esophageal lipoma: a case report. Dis. Esophagus 2016; 29: 1167–1169. 10.1111/dote.12400 PubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Background: Protein phosphatase 4 (PP4) has been reported to be deeply involved in the development of malignancy. Protein phosphatase 4 regulatory subunit 1 (PP4R1) is an indispensable subunit of PP4, but its function in tumors remains unclear. In this study, we investigated the role of PP4R1 in non -small cell lung cancer (NSCLC). Method: Based on clinical samples and clinical data of NSCLC from the cancer genome atlas (TCGA) database, we first explored the role of PP4R1 in NSCLC. Next, we constructed PP4R1-overexpressed NSCLC cell lines (H1299 and A549), and explored the effects of PP4R1 on colony- and sphere-forming capacities. Subsequently, we performed RNA-seq and enrichment analyses, combined with corresponding rescue experiments, to further explore the underlying mechanisms by which PP4R1 affects the progression of NSCLC. Results: PP4R1 was significantly hyper-expressed in cancerous tissues from NSCLC patients, and higher PP4R1 level was negatively related to the overall survival of NSCLC patients. Cellular experiments proved that overexpressing PP4R1 promoted the cell mobility, colony-forming, and sphere-forming abilities of H1299 and A549 cells. Overexpression of PP4R1 led to the hyper-expression of octamer-binding transcription factor 4 (OCT4) and the activation of the mitogen-activated protein kinases/extracellular regulated kinase (MAPK/ERK) signaling pathway. Application of the mitogen-activated extracellular signalregulated kinase (MEK) inhibitor, U0126, significantly reversed the activation of ERK and the PP4R1-promoted cell mobility, cell growth, and sphere-forming abilities. Conclusion: In summary, PP4R1 upregulated the expression of OCT4 via the MAPK/ERK signaling pathway, and induced cancer stemness to promote cancer cell progression.

Background: Globally, non-small cell lung cancer (NSCLC) is a leading factor in cancer-related mortality. Additionally, the Geriatric Nutritional Risk Index (GNRI) has been assessed as a predictive and prognostic indicator in various types of carcinomas. Our study aims to assess the prognostic importance of GNRI computed at diagnosis in NSCLC patients receiving immune checkpoint inhibitors (ICIs). Methods: The study evaluated 148 patients who underwent immunotherapy for NSCLC from January 1, 2018, through December 31, 2021, retrospectively. Patients combined with other malignant tumors or severe comorbidities were excluded from the study. The receiver operating characteristic (ROC) curve was employed in regulating the ideal cutoff worth of GNRI. Survival outcomes were evaluated through Kaplan-Meier analysis. Following this, both univariate and multivariate analyses were conducted utilizing Cox regression analysis to identify any potential factors that may influence the survival outcomes. Results: The cutoff point for GNRI was 108.15 [area under the curve (AUC) =0.575, P=0.048]. Further analysis using the Kaplan-Meier method demonstrated that individuals in the high GNRI group had significantly longer progression-free survival (PFS) and overall survival (OS) compared to those in the low GNRI group (P=0.02, P=0.01). The further stratified study showed that GNRI had greater predictive value in tumor node metastasis (TNM) stage II-III and elderly (age >= 65 years) NSCLC patients undergoing ICI therapy. The multivariate Cox regression analysis indicated that GNRI [hazard ratio (HR): 0.536, P=0.03], obesity (HR: 16.283, P<0.001), and surgical history (HR: 0.305, P<0.001) were associated with poorer survival rates. Conclusions: Among patients undergoing ICI therapy for NSCLC, GNRI is an effective independent prognostic indicator, and a high GNRI at diagnosis is substantially related with longer PFS and OS. The incorporation of GNRI in pre-treatment evaluations within clinical settings is beneficial.

Protein phosphatase 4 (PP4) plays an indispensable regulatory part in the development and malignant progression of multifarious tumors. Nevertheless, the function of protein phosphatase 4 regulatory subunit 1 (PP4R1), a vital regulatory subunit of PP4, in tumors especially in lung cancer remains blurred. Therefore, this study aimed to investigate the function and mechanism of PP4R1 in the development of non-small cell lung cancer (NSCLC). We analyzed the clinical correlation of PP4R1 based on the TCGA database by UALCAN (https://ualcan.path.uab.edu/index.html) and found that hyper-expression of PP4R1 mRNA was related to the severe prognosis in NSCLC. The subsequent cellular experiments confirmed that the proliferation, colony growth, migration as well as invasion of H1299 and HCC827 were significantly enhanced after PP4R1 overexpression treatment in vitro. Results from animal experiments pointed out that tumors exhibited stronger growth and lung metastatic capacities due to the overexpression of PP4R1. The bioinformatics analysis, including RNA-seq, showed us that PP4R1 significantly promoted the expression of several HSP70 family member genes, with a particularly marked increase in HSPA6, and the enrichment analyses illustrated that the differentially expressed genes (DEGs) were enriched in those pathways related to protein folding. More importantly, the overexpression of HSPA6 resulted in the same malignant progression of NSCLC as PP4R1 overexpression, and both concomitant with the activation of endoplasmic reticulum (ER) stress. In aggregate, PP4R1 contributed to the malignant progression of NSCLC via up-regulating HSPA6 expression and then activating ER stress.

Background CircRNA is recognized for its significant regulatory function across various cancers. However, its regulatory role in non-small cell lung cancer (NSCLC) is still largely uncharted. Methods Analysis based on public databases is completed using R software. circATP9A was identified by two circRNA datasets of NSCLC from the Gene Expression Omnibus database. To examine the impact of circATP9A on the phenotype of NSCLC, we conducted both in vitro and in vivo functional experiments. The mRNA and protein levels of specific molecules were determined through quantitative real-time PCR and western blot assays. RNA pulldown and RNA immunoprecipitation assays were performed to verify the interaction between RNA and protein. The functional role of extracellular vesicles (EVs)-circATP9A on tumor-associated macrophage (TAM) polarization was assessed using co-culture system and cell flow cytometry. Results Here, we elucidates the functional role of circATP9A in NSCLC. We demonstrated that circATP9A can foster the progression of NSCLC through in vivo and in vitro experiments. From a mechanistic standpoint, circATP9A can interact with the HuR protein to form an RNA–protein complex, subsequently amplifying the mRNA and protein levels of the target gene NUCKS1. Further, the PI3K/AKT/mTOR signaling was identified as the downstream pathways of circATP9A/HuR/NUCKS1 axis. More notably, hnRNPA2B1 can mediate the incorporation of circATP9A into EVs. Subsequently, these EVs containing circATP9A induce the M2 phenotype of TAMs, thereby facilitating NSCLC development. Conclusions Our discoveries indicate that circATP9A could serve as a promising diagnostic indicator and a therapeutic target for NSCLC.

Objective Costimulatory molecules have been demonstrated to exert essential roles in multiple cancers. However, their role in lung cancer remains elusive. Here, we sought to identify costimulatory molecule-related lncRNAs in non-small cell lung cancer (NSCLC) and establish a prognostic signature to predict the prognosis of patients with NSCLC. Methods A total of 535 lung adenocarcinoma (LUAD) and 502 lung squamous cell carcinoma (LUSC) patients from the cancer genome atlas (TCGA) database were recruited. A novel costimulatory molecule-based lncRNA prognostic model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm to predict the overall survival. The Homo_sapiens.GRCh38 data set was set as a reference file for probe annotation. Results A total of 593 costimulatory molecule-related lncRNAs were extracted. After analysis, six costimulatory molecule-related lncRNAs (AC084859.1, AC079949.2, HSPC324, LINC01150, LINC01150, and AC090617.5) were screened. A prognostic model based on the six lncRNAs was established using systematic bioinformatics analyses. The prognostic model had a prognostic value in NSCLC patients. Furthermore, a prognostic nomogram was established based on clinical parameters and a risk-score model. Patients with different risk scores had considerably different tumor-infiltrating immune cells, somatic mutational loading, clinical outcomes, signaling pathways, and immunotherapy efficacy. In addition, LINC01137 was associated with unfavorable disease outcomes and fueled tumor progression in NSCLC. Conclusion Taken together, our study demonstrated that a costimulatory molecule-related lncRNA model could be a potential prognostic biomarker in NSCLC. Moreover, LINC01137 could facilitate the proliferation and invasion of lung cancer.

Lung cancer is one of the malignant tumors with the highest incidence and mortality rate worldwide and has a poor prognosis. With the popularization of thin layer CT, more and more early lung cancers are being detected. In recent years, thoracoscopic technology and robotic surgery technology have been innovated, and multiple adjuvant therapies such as chemotherapy, targeted therapy and immunotherapy have progressed rapidly, providing lung cancer patients with multiple treatment options. However, the prognosis of lung cancer patients has not been significantly improved, which is related to the overall poor prognosis of lung cancer patients on the one hand, and the urgent need to find effective predictive markers for patients' prognosis, to accurately screen patients, and to carry out targeted treatment in order to improve patients' prognosis on the other hand. In this paper, we review the progress of tertiary lymphoid structures (TLSs) in lung cancer and discuss the prognostic predictive value of TLSs in lung cancer and their feasibility as biomarkers for adjuvant therapy.