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Abstract Background 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. Methods 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. Results 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. Conclusion 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.

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non‐small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. Methods: By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single‐cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. Results: LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo‐keto reductases, glutathione S‐transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer‐associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non‐MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. Conclusions: These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype‐specific treatment strategies. [ABSTRACT FROM AUTHOR]

Objective To explore the mechanism and effects of Basonuclin 1(BNC1) on the migration and invasion abilities of lung squamous cell carcinoma. Methods Bioinformatics technology was used to analyze the expression patterns and survival impact of BNC1 in patients with lung squamous cell carcinoma in online databases; Tissue microarrays were stained by immunohistochemistry assay and analyzed for BNC1 protein level. Cell lines for lung squamous cell carcinoma with high and low BNC1 expression were screened in the Cancer Cell Line Encyclopedia (CCLE) database. Wound healing experiment and transwell assay were performed on lung squamous cell carcinoma cell models with knockdown and overexpression of BNC1, and the migration and invasion rates of each cell line were detected; Quantitative reverse transcription PCR(RT-qPCR) was used to validate the migration and invasion of 10 highly related genes derived from literature. Western blotting was used to validate the selected regulatory genes. Results Bioinformatics technology found that BNC1 was highly expressed in lung squamous cell carcinoma tissues and was associated with lower survival rate(P=0.047). The expression of BNC1 in lung squamous cell carcinoma was higher than that in paracancerous tissues (P < 0.05). BNC1 had higher expression in the H226 cells and lower expression in the SK-MES1 cells. BNC1 knockdown inhibited the migration and invasion abilities of lung squamous cell carcinoma cells(P < 0.05), and BNC1 overexpression enhanced the migration and invasion abilities of lung squamous cell carcinoma cells(P < 0.05). Screening of BNC1 downstream regulatory molecules at the mRNA level showed that CDH1 was decreased when BNC1 was overexpressed (P < 0.05), and increased when BNC1 was knocked down (P < 0.05). The results of mRNA level were consistent with the results verified by Western blotting (P < 0.05). Conclusion BNC1 may be a gene predicting poor prognosis for lung squamous cell carcinoma patients, and BNC1 may likely to promote cell migration and invasion of lung squamous cell carcinoma by downregulating CDH1 expression.

Background The purpose of our study was to construct a prognostic model based on ferroptosis-related gene signature to improve the prognosis prediction of lung squamous carcinoma (LUSC).

Abstract Background Inflammation is known to have an intricate relationship with tumorigenesis and tumor progression while it is also closely related to tumor immune microenvironment. Whereas the role of inflammation‐related genes (IRGs) in lung squamous carcinoma (LUSC) is barely understood. Herein, we recognized IRGs associated with overall survival (OS), built an IRGs signature for risk stratification and explored the impact of IRGs on immune infiltration landscape of LUSC patients. Methods The RNA‐sequencing and clinicopathological data of LUSC patients were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, which were defined as training and validation cohorts. Cox regression and least absolute shrinkage and selection operator analyses were performed to build an IRG signature. CIBERSORT, microenvironment cell populations‐counter and tumor immune dysfunction and rejection (TIDE) algorithm were used to perform immune infiltration analysis. Results A two‐IRG signature consisting of KLF6 and SGMS2 was identified according to the training set, which could categorize patients into two different risk groups with distinct OS. Patients in the low‐risk group had more anti‐tumor immune cells infiltrated while patient with high‐risk had lower TIDE score and higher levels of immune checkpoint molecules expressed. The IRG signature was further identified as an independent prognostic factor of OS. Subsequently, a prognostic nomogram including IRG signature, age, and cancer stage was constructed for predicting individualized OS, whose concordance index values were 0.610 (95% CI: 0.568–0.651) in the training set and 0.652 (95% CI: 0.580–0.724) in validation set. Time‐dependent receiver operator characteristic curves revealed that the nomogram had higher prediction accuracy compared with the traditional tumor stage alone. Conclusion The IRG signature was a predictor for patients with LUSC and might serve as a potential indicator of the efficacy of immunotherapy. The nomogram based on the IRG signature showed a relatively good predictive performance in survival.

Cancer is more alarming in modern days due to its identification at later stages. Among cancers, lung, liver and colon cancers are the leading cause of untimely death. Manual cancer identification from histopathological images is time‐consuming and labour‐intensive. Thereby, computer‐aided decision support systems are desired. A deep learning model is proposed in this paper to accurately identify cancer. Convolutional neural networks have shown great ability to identify the significant patterns for cancer classification. The proposed Parallel, Cross Concatenated and Grouped Convolutions Deep Neural Network (PC2GCDN2) has been developed to obtain accurate patterns for classification. To prove the robustness of the model, it is evaluated on the KMC and TCGA‐LIHC liver dataset, LC25000 dataset for lung and colon cancer classification. The proposed PC2GCDN2 model outperforms states‐of‐the‐art methods. The model provides 5.5% improved accuracy compared to the LiverNet proposed by Aatresh et. al on the KMC dataset. On the LC25000 dataset, 2% improvement is observed compared to existing models. Performance evaluation metrics like Sensitivity, Specificity, Recall, F1‐Score and Intersection‐Over‐Union are used to evaluate the performance. To the best of our knowledge, PC2GCDN2 can be considered as gold standard for multiple histopathology image classification. PC2GCDN is able to classify the KMC and TCGA‐LIHC liver dataset with 96.4% and 98.6% accuracy, respectively, which are the best results obtained till now. The performance has been superior on LC25000 dataset with 99.5% and 100% classification accuracy on lung and colon dataset, by utilizing less than 0.5 million parameters. [ABSTRACT FROM AUTHOR]

Abstract Background Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic disease that involves the infiltration of IgG4-positive plasma cells in multiple organs. Kimura disease (KD) presents as subcutaneous masses on the head and neck, frequently accompanied by eosinophilia and high immunoglobulin E (IgE) levels. Here, we report a rare case of concurrence of IgG4-RD and KD with manifestations of asthma, pulmonary embolism, and central diabetes insipidus accompanied by lung carcinoma. Case presentation A 65-year-old Chinese male with an eight-year history of KD was admitted to our hospital with complaints of dyspnea and expectoration for one month. Laboratory examination showed a considerable elevation in the serum eosinophil count and total IgE and IgG4 levels. Chest enhanced computed tomography showed filling defects in the right pulmonary artery and a nodule in the left inferior lobe. Pancreatic enhanced magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography showed a swollen pancreatic tail and local stricture of the pancreatic duct section of the common bile duct. Enhanced MRI of the pituitary gland showed thickening of the pituitary stalk. Additionally, immunohistochemistry of the specimens collected eight years prior revealed IgG4-positive cells. Following the diagnosis of IgG4-RD with KD, glucocorticoids with immunosuppressants were initiated; there was a prompt improvement in the patient’s condition. One-year post-discharge, the patient underwent wedge-shaped resection of the lung due to enlargement of the pulmonary nodule, and the pathology revealed lung squamous carcinoma. Conclusions This case presents a rare clinical condition in which the concurrence of IgG4-RD and KD causes various rare manifestations including asthma, pulmonary embolism, central diabetes insipidus, and complicated lung carcinoma. This highlights the importance of monitoring for malignancies in IgG4-RD patients during follow-up.

Background: Inflammation is known to have an intricate relationship with tumorigenesis and tumor progression while it is also closely related to tumor immune microenvironment. Whereas the role of inflammation‐related genes (IRGs) in lung squamous carcinoma (LUSC) is barely understood. Herein, we recognized IRGs associated with overall survival (OS), built an IRGs signature for risk stratification and explored the impact of IRGs on immune infiltration landscape of LUSC patients. Methods: The RNA‐sequencing and clinicopathological data of LUSC patients were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, which were defined as training and validation cohorts. Cox regression and least absolute shrinkage and selection operator analyses were performed to build an IRG signature. CIBERSORT, microenvironment cell populations‐counter and tumor immune dysfunction and rejection (TIDE) algorithm were used to perform immune infiltration analysis. Results: A two‐IRG signature consisting of KLF6 and SGMS2 was identified according to the training set, which could categorize patients into two different risk groups with distinct OS. Patients in the low‐risk group had more anti‐tumor immune cells infiltrated while patient with high‐risk had lower TIDE score and higher levels of immune checkpoint molecules expressed. The IRG signature was further identified as an independent prognostic factor of OS. Subsequently, a prognostic nomogram including IRG signature, age, and cancer stage was constructed for predicting individualized OS, whose concordance index values were 0.610 (95% CI: 0.568–0.651) in the training set and 0.652 (95% CI: 0.580–0.724) in validation set. Time‐dependent receiver operator characteristic curves revealed that the nomogram had higher prediction accuracy compared with the traditional tumor stage alone. Conclusion: The IRG signature was a predictor for patients with LUSC and might serve as a potential indicator of the efficacy of immunotherapy. The nomogram based on the IRG signature showed a relatively good predictive performance in survival. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the impact that TTN mutation had on the gene heterogeneity expression and prognosis in patients with lung adenocarcinoma.MethodsIn this study, the Cancer Genome Atlas (TCGA) dataset was used to analyze the TTN mutations in lung adenocarcinoma. Lung adenocarcinoma data was collected from the TCGA database, clinical information of patients was analyzed, and bioinformatics statistical methods were applied for mutation analysis and prognosis survival analysis. The results were verified using the GEO dataset.ResultsThe incidence of TTN mutations in lung adenocarcinoma was found to be 73%, and it was related to the prognosis of lung adenocarcinoma. Ten genes were screened with significant contributions to prognosis. A prognosis model was constructed and verified by LASSO COX analysis in the TCGA and GEO datasets based on these ten beneficial factors. The independent prognostic factor H2BC9 for TTN mutation-driven gene heterogeneity expression was screened through multi-factor COX regression analysis.ConclusionOur data showed that the gene heterogeneity expression, which was driven by TTN mutations, prolonged the survival of lung adenocarcinoma patients and provided valuable clues for the prognosis of TTN gene mutations in lung adenocarcinoma.

There is still no ideal predictive biomarker for immunotherapy response among patients with non-small cell lung cancer. Costimulatory molecules play a role in anti-tumor immune response. Hence, they can be a potential biomarker for immunotherapy response. The current study comprehensively investigated the expression of costimulatory molecules in lung squamous carcinoma (LUSC) and identified diagnostic biomarkers for immunotherapy response. The costimulatory molecule gene expression profiles of 627 patients were obtained from the The Cancer Genome Atlas, GSE73403, and GSE37745 datasets. Patients were divided into different clusters using the k-means clustering method and were further classified into two discrepant tumor microenvironment (TIME) subclasses (hot and cold tumors) according to the immune score of the ESTIMATE algorithm. A high proportion of activated immune cells, including activated memory CD4 T cells, CD8 T cells, and M1 macrophages. Five CMGs (FAS, TNFRSF14, TNFRSF17, TNFRSF1B, and TNFSF13B) were considered as diagnostic markers using the Least Absolute Shrinkage and Selection Operator and the Support Vector Machine-Recursive Feature Elimination machine learning algorithms. Based on the five CMGs, a diagnostic nomogram for predicting individual tumor immune microenvironment subclasses in the TCGA dataset was developed, and its predictive performance was validated using GSE73403 and GSE37745 datasets. The predictive accuracy of the diagnostic nomogram was satisfactory in all three datasets. Therefore, it can be used to identify patients who may benefit more from immunotherapy. [ABSTRACT FROM AUTHOR]

Cr(VI) is broadly applied in industry. Cr(VI) exposure places a big burden on public health, thereby increasing the risk of lung squamous cell carcinoma (LUSC). The mechanisms underlying Cr(VI)‐induced LUSC remain largely elusive. Here, we report that the cancer stem cell (CSC)/tumour‐initiating cell (TIC)‐like subgroup within Cr(VI)‐transformed bronchial epithelial cells (CrT) promotes lung cancer tumourigenesis. Mechanistically, Cr(VI) exposure specifically increases the expression levels of aldehyde dehydrogenase 1A1 (ALDH1A1), a CSC marker, through KLF4‐mediated transcription. ALDH1A1 maintains self‐renewal of CrT/TICs and facilitates the expression and secretion of EGF from CrT/TICs, which subsequently promotes the activation of EGFR signalling in differentiated cancer cells and tumour growth of LUSC. In addition, the ALDH1A1 inhibitor A37 and gemcitabine synergistically suppress LUSC progression. Importantly, high ALDH1A1 expression levels are positively correlated with advanced clinical stages and predict poor survival in LUSC patients. These findings elucidate how ALDH1A1 modulates EGF secretion from TICs to facilitate LUSC tumourigenesis, highlighting new therapeutic strategies for malignant lung cancers. [ABSTRACT FROM AUTHOR]

Background: At present, immunotherapy is a very promising treatment method for lung cancer patients, while the factors affecting response are still controversial. It is crucial to predict the efficacy of lung squamous carcinoma patients who received immunotherapy. Methods: In our retrospective study, we enrolled lung squamous carcinoma patients who received immunotherapy at Beijing Chest Hospital from January 2017 to November 2021. All patients were grouped into two cohorts randomly, the training cohort (80% of the total) and the test cohort (20% of the total). The training cohort was used to build neural network models to assess the efficacy and outcome of immunotherapy in lung squamous carcinoma based on clinical information. The main outcome was the disease control rate (DCR), and then the secondary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: A total of 289 patients were included in this study. The DCR model had area under the receiver operating characteristic curve (AUC) value of 0.9526 (95%CI, 0.9088-0.9879) in internal validation and 0.9491 (95%CI, 0.8704-1.0000) in external validation. The ORR model had AUC of 0.8030 (95%CI, 0.7437-0.8545) in internal validation and 0.7040 (95%CI, 0.5457-0.8379) in external validation. The PFS model had AUC of 0.8531 (95%CI, 0.8024-0.8975) in internal validation and 0.7602 (95%CI, 0.6236-0.8733) in external validation. The OS model had AUC of 0.8006 (95%CI, 0.7995-0.8017) in internal validation and 0.7382 (95%CI, 0.7366-0.7398) in external validation. Conclusions: The neural network models show benefits in the efficacy evaluation of immunotherapy to lung squamous carcinoma patients, especially the DCR and ORR models. In our retrospective study, we found that neoadjuvant and adjuvant immunotherapy may bring greater efficacy benefits to patients. [ABSTRACT FROM AUTHOR]

This study examined the internal mechanism of miR-210-3p/CELF2 in LUSC. Expression data of mRNAs and miRNAs in LUSC were acquired from TCGA and subjected to differential expression analysis. qRT-PCR was applied to examine miR-210-3p and CELF2 expression. Besides, western blot was utilized to evaluate protein expression of CELF2 and PI3K/AKT pathway-related proteins. Dual-luciferase reporter analysis was conducted to validate targeting relationship between miR-210-3p and CELF2. Additionally, CCK-8, colony formation, transwell and flow cytometry were employed to respectively test proliferation, migration, invasion abilities and cell cycle distribution. Xenograft tumor models were used to evaluate the influence of miR-210-3p and CELF2 on tumor growth. MiR-210-3p was highly expressed, while CELF2 was less expressed in LUSC cells. Besides, miR-210-3p could downregulate CELF2 expression. Cell functional assay verified that miR-210-3p accelerated aggressive behaviors of LUSC cells. Additionally, rescue assay suggested that miR-210-3p downregulated CELF2 level to stimulate LUSC cell phenotypes and cell cycle progression through PI3K/AKT pathway. Moreover, miR-210-3p/CELF2 stimulated the tumor growth in vivo. To sum up, miR-210-3p modulated CELF2 expression, thus affecting cell phenotypes and cell cycle distribution in LUSC through PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Tetrastigma hemsleyanum （ T. hemsleyanum ）, valued in traditional medicine for its potential to boost immunity and combat tumors, contains uncharacterized active compounds and mechanisms. This represents a significant gap in our understanding of its ethnopharmacological relevance. To involve the mechanism of anti-lung cancer effect of T. hemsleyanum by means of experiment and bioinformatics analysis. The anticancer mechanism of T. hemsleyanum against lung squamous carcinoma (LUSC) in zebrafish was investigated. The LUSC model was established by injecting NCI–H2170 cells in the zebrafish and evaluating its anti-tumor efficacy. Next, component targets and key genes were obtained by molecular complex detection (MCODE) analysis and protein-protein interaction (PPI) network analysis. Component analysis of T. hemsleyanum was performed by UPLC-Q-TOF-MS. Molecular docking was used to simulate the binding activities of key potential active components to core targets were simulated using. Prognostic and pan-cancer analyses were then performed to validate the signaling pathways involved in the prognostic genes using gene set enrichment analysis (GSEA). Subsequently, Molecular dynamics simulations were then performed for key active components and core targets. Finally, cellular experiments were used to verify the expression of glutamate metabotropic receptor 3 (GRM3) and glutamate metabotropic receptor 7 (GRM7) in the anticancer effect exerted of T. hemsleyanum. We experimentally confirmed the inhibitory effect of T. hemsleyanum on LUSC by transplantation of NCI–H2170 cells into zebrafish. There are 20 main compounds in T. hemsleyanum , such as procyanidin B1, catechin, quercetin, and kaempferol, etc. A total of 186 component targets of T. hemsleyanum and sixteen hub genes were screened by PPI network and MCODE analyses. Molecular docking and molecular dynamics simulation results showed that Gingerglycolipid B and Rutin had higher affinity with GRM3 and GRM7 , respectively. Prognostic analysis, Pan-cancer analysis and verification experiment also confirmed that GRM3 and GRM7 were targets for T. hemsleyanum to exert anti-tumor effects and to participate in immune and mutation processes. In vitro experiments suggested that the inhibitory effect of T. hemsleyanum on cancer cells was correlated with GRM3 and GRM7. In vivo, in vitro and in silico results confirmed the potential anticancer effects against LUSC of T. hemsleyanum , which further consolidated the claim of its traditional uses. [Display omitted] • A total of 20 compounds and 16 hub genes linked to T. hemsleyanum 's LUSC inhibition were identified. • Molecular studies reveal Gingerglycolipid B and Rutin have high affinity for GRM3 and GRM7. • GRM3 and GRM7 were potential T. hemsleyanum targets for antitumor activity. [ABSTRACT FROM AUTHOR]

Lung squamous carcinoma (LUSC) is a malignant tumor of the respiratory system with highly heterogeneous characteristics. Lactate is the main product of aerobic glycolysis during the metabolic reprogramming of tumors. There is growing evidence that lactate metabolic processes have a broad and sophisticated impact on tumor phenotypic plasticity and tumor microenvironment (TME). However, the pattern of lactate metabolism in patients with LUSC and its impact on TME, phenotype, prognosis, and treatment have not been fully elucidated. In this study, we identified two subtypes with different lactate metabolism patterns in LUSC by non-negative matrix factorization and explored their multi-omics features. We observed that lactate metabolism levels in LUSC extensively influenced tumor immune infiltration patterns, adaptation to the hypoxia environment, and energy metabolic reprogramming. Subsequently, we constructed the lactate metabolism-related prognostic index (LMRPI) using Cox stepwise regression analysis. LMRPI showed excellent stability and accuracy, and based on the median value of LMRPI, LUAD were divided into two subgroups. The two subgroups have different patterns of immune infiltration and somatic mutations. Meanwhile, the two subgroups had different responsiveness to immune checkpoint inhibitor (ICI) therapies and different sensitivity to various chemotherapeutic and molecular targeting agents. In conclusion, we defined two subtypes with different lactate metabolism patterns in LUSC and extensively characterized their multi-omics profile. Furthermore, we developed LMRPI that predicts the prognosis of LUSC patients while also predicting their response to various adjuvant therapies, including immunotherapy, to guide their individualized treatment.

Abstract Cr(VI) is broadly applied in industry. Cr(VI) exposure places a big burden on public health, thereby increasing the risk of lung squamous cell carcinoma (LUSC). The mechanisms underlying Cr(VI)‐induced LUSC remain largely elusive. Here, we report that the cancer stem cell (CSC)/tumour‐initiating cell (TIC)‐like subgroup within Cr(VI)‐transformed bronchial epithelial cells (CrT) promotes lung cancer tumourigenesis. Mechanistically, Cr(VI) exposure specifically increases the expression levels of aldehyde dehydrogenase 1A1 (ALDH1A1), a CSC marker, through KLF4‐mediated transcription. ALDH1A1 maintains self‐renewal of CrT/TICs and facilitates the expression and secretion of EGF from CrT/TICs, which subsequently promotes the activation of EGFR signalling in differentiated cancer cells and tumour growth of LUSC. In addition, the ALDH1A1 inhibitor A37 and gemcitabine synergistically suppress LUSC progression. Importantly, high ALDH1A1 expression levels are positively correlated with advanced clinical stages and predict poor survival in LUSC patients. These findings elucidate how ALDH1A1 modulates EGF secretion from TICs to facilitate LUSC tumourigenesis, highlighting new therapeutic strategies for malignant lung cancers.

Cancer immunotherapy is an increasingly successful strategy for treating patients with advanced or conventionally drug-resistant cancers. T cells have been proved to play important roles in anti-tumor and tumor microenvironment shaping, while these roles have not been explained in lung squamous cell carcinoma (LUSC). In this study, we first performed a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data from the gene expression omnibus (GEO) database to identify 72 T-cell marker genes. Subsequently, we constructed a 5- gene prognostic signature in the training cohort based on the T-cell marker genes from the cancer genome atlas (TCGA) database, which was further validated in the testing cohort and GEO cohort. The areas under the receiver operating characteristic curve at 1-, 3-, and 5-years were 0.614, 0.713 and 0.702 in the training cohort, 0.669, 0.603 and 0.645 in the testing cohort, 0.661, 0.628 and 0.590 in the GEO cohort, respectively. Furthermore, we created a highly reliable nomogram to facilitate clinical application. Gene set enrichment analysis showed that immune-related pathways were mainly enriched in the high-risk group. Tumor immune microenvironment indicated that high-risk group exhibited higher immune score, stromal score, and immune cell infiltration levels. Moreover, genes of the immune checkpoints and human leukocyte antigen family were all overexpressed in high-risk group. Drug sensitivity revealed that low-risk groupwas sensitive to 8 chemotherapeutic drugs and high-risk group to 4 chemotherapeutic drugs. In short, our study reveals a novel prognostic signature based on T-cell marker genes, which provides a new target and theoretical support for LUSC patients. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic disease that involves the infiltration of IgG4-positive plasma cells in multiple organs. Kimura disease (KD) presents as subcutaneous masses on the head and neck, frequently accompanied by eosinophilia and high immunoglobulin E (IgE) levels. Here, we report a rare case of concurrence of IgG4-RD and KD with manifestations of asthma, pulmonary embolism, and central diabetes insipidus accompanied by lung carcinoma.Case Presentation: A 65-year-old Chinese male with an eight-year history of KD was admitted to our hospital with complaints of dyspnea and expectoration for one month. Laboratory examination showed a considerable elevation in the serum eosinophil count and total IgE and IgG4 levels. Chest enhanced computed tomography showed filling defects in the right pulmonary artery and a nodule in the left inferior lobe. Pancreatic enhanced magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography showed a swollen pancreatic tail and local stricture of the pancreatic duct section of the common bile duct. Enhanced MRI of the pituitary gland showed thickening of the pituitary stalk. Additionally, immunohistochemistry of the specimens collected eight years prior revealed IgG4-positive cells. Following the diagnosis of IgG4-RD with KD, glucocorticoids with immunosuppressants were initiated; there was a prompt improvement in the patient's condition. One-year post-discharge, the patient underwent wedge-shaped resection of the lung due to enlargement of the pulmonary nodule, and the pathology revealed lung squamous carcinoma.Conclusions: This case presents a rare clinical condition in which the concurrence of IgG4-RD and KD causes various rare manifestations including asthma, pulmonary embolism, central diabetes insipidus, and complicated lung carcinoma. This highlights the importance of monitoring for malignancies in IgG4-RD patients during follow-up. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: To evaluate the ability of dual-energy CT(DECT)-based quantitative parameters and radiomics features to differentiate solid lung adenocarcinoma (ADC) from squamous cell carcinoma (SCC)., Methods: This study included 213 patients diagnosed with ADC and SCC who underwent DECT scans at two centers from November 2022 to December 2023. Patients at center 1 were randomly divided into training (n = 114) and internal test set (n = 50) in a 7:3 ratio, with center 2 serving as the external test set (n = 49). Radiologic and clinical data were combined to establish a clinical-radiologic model. Ten types of DECT energy images including conventional images, iodine density (ID), effective atomic number (Z eff ), electron density, and virtual mono-energetic images (VMI) were reconstructed in both arterial phases (AP) and venous phases (VP). Quantitative parameters were measured at the uniform enhanced solid portion of the tumor and normalized to the aorta, used to develop a quantification model and calculate the quantitative score (quantscore). Radiologists manually delineated the tumor ROI at the largest level for extracting radiomics features in these 10 energy images. These features were used to establish 10 uni-energy models from which the best-performing features were selected to construct the final radiomics model and calculate a radiomics score (radscore). Then, a combined model was developed using the akaike information criterion(AIC) and compared to the clinical-radiological model to test its diagnostic validity., Results: The independent predictors of the clinical-radiological model included age, gender, and central or peripheral location, and the AUCs for the training set, internal test set, and external test set were 0.808, 0.837, and 0.802. The quantification model incorporated 40 keV CT values, Z eff , normalized Z eff , and the slope of the spectral attenuation curve (λHU) in the AP and normalized ID, Z eff , and λHU in the VP. Uni-energy models based on AP ID maps, AP Z eff maps, and VP VMI 65 keV significantly outperformed AUC= 0.5, and 11 radiomics features were selected from these three models to construct the final radiomics model. The combined model, incorporating age, gender, quantscore, and radscore, significantly outperformed the clinical-radiological model in the training set (AUC=0.952 vs 0.808, P < 0.001), and demonstrated higher performance in both the internal and external test sets, although these differences did not reach statistical significance (AUC=0.870 vs 0.837, for the internal test set [P = 0.542], 0.888 vs 0.802 for the external test sets [P = 0.128]). The evaluation of the combined model demonstrated good discriminative ability and potential for generalization., Conclusion: The combined model, integrating quantitative parameters and radiomics features from DECT multi-energy images with clinical-radiological characteristics, can be used as a non-invasive tool to differentiate ADC from SCC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Minjing Zuo reports financial support was provided by Jiangxi Provincial Department of Education. Minjing Zuo reports financial support was provided by Jiangxi Provincial Department of Science and Technology., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Lung cancer continues to be a prevalent cause of cancer-related deaths worldwide, with lung squamous carcinoma (LUSC) being a significant subtype characterized by comparatively low survival rates. Extensive molecular studies on LUSC have been conducted; however, the clinical importance of cell-cycle-associated genes has rarely been examined. This study aimed to investigate the relationship between these genes and LUSC., Methods: The expression trends of genes related to the cell cycle in a group of patients with LUSC were analyzed. Clinical information and mRNA expression data were obtained from The Cancer Genome Atlas via cBioportal. Multiple analyses have been performed to investigate the association between these genes and LUSC., Results: Three clusters were identified based on the mRNA expression of 124 cell cycle-associated genes. Cluster 3 exhibited the worst prognosis. A comparative analysis showed that nine expressed genes differed distinctly among all the clusters. Among these nine genes, elevated expression of CDK4 was strongly associated with positive prognosis. Furthermore, the expression of ANAPC11, ANAPC5, and ORC4 correlated with the advancement of LUSC pathological stages., Conclusions: Gene expression profiles associated with the cell cycle across various LUSC subtypes were identified, highlighting that specific genes are related to prognosis and disease stages. Based on these results, new prognostic strategies, patient stratification, and targeted therapy trials have been conducted for LUSC., (© 2024 John Wiley & Sons Ltd.)

Abstract Background Clinical options for lung squamous carcinoma (LUSC) are still quite limited. Carcinogenesis is an exceedingly complicated process involving multi-level dysregulations. Therefore, only looking into one layer of genomic dysregulation is far from sufficient. Methods We identified differentially expressed genes with consistent upstream genetic or epigenetic dysregulations in LUSC. Random walk was adopted to identify genes significantly affected by upstream abnormalities. Expression differentiation and survival analysis were conducted for these significant genes, respectively. Prognostic power of selected gene was also tested in 102 male LUSC samples through immunohistochemistry assay. Results Twelve genes were successfully retrieved from biological network, including ERα (ESRS1), EGFR, AR, ATXN1, MAPK3, PRKACA, PRKCA, SMAD4, TP53, TRAF2, UBQLN4 and YWHAG, which were closely related to sex hormone signaling pathway. Survival analysis in public datasets indicated ERα was significantly associated with a poor overall survival (OS) in male LUSC. The result of our immunohistochemistry assay also demonstrated this correlation using R0 resected tumors (n = 102, HR: 2.152, 95% CI: 1.089–4.255, p = 0.024). Although disease-free survival (DFS) difference was non-significant (n = 102, p = 0.12), the tendency of distinction was straight-forward. Cox analysis indicated ERα was the only independent prognostic factor for male patients’ OS after R0 resection (HR = 2.152, p = 0.037). Conclusion ERα was significantly related to a poor prognosis in LUSC, especially for male patients after radical surgery, confirmed by our immunohistochemistry data.

Abstract The development of targeted therapies that inhibit cancer-driving oncogenes has improved outcomes of patients diagnosed with lung adenocarcinoma (LUAD). In contrast, patients diagnosed with lung squamous cell carcinoma (LUSC) suffer worse survival outcomes and lack effective targeted treatment options. Identification of molecular drivers of LUSC to support development of targeted treatments is urgently needed. Addressing this need, the current report introduces the novel cancer gene SLIT- and NTRK-like family member 3 (SLITRK3) and its role in activating the neurotrophic receptor tyrosine kinase 3 (NTRK3) in LUSC cells. Multiple genome-wide data sets from patient samples were produced by us or downloaded from public databases to analyze tumor gene copy number aberrations, mRNA expression and associated survival outcomes. An accompanying mechanistic study employed LUSC cell lines and multiple methods, including in situ immunofluorescence, sphere-formation assay, and fluorescence-activated cell sorting analysis of the CD133-positive cell fraction. Altogether, the results indicate that gene amplification and consequent high expression of SLITRK3 in LUSC is associated with worse outcomes and induces SLITRK3-dependent activation of NTRK3 to promote a cancer stem cell phenotype that is inhibited by existing NTRK-targeted inhibitors. Based on a recent literature search, this is the first report of a mechanistic role for SLITRK3 in cancer.

BackgroundNon-small cell lung cancer (NSCLC) is a malignant tumor with high mortality. Lung squamous carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the common subtypes of NSCLC. However, how LUSC and LUAD are compatible remains to be elucidated.MethodsWe used a network approach to find highly interconnected genes shared with LUSC and LUAD, and we then built modules to assess the degree of preservation between them. To quantify this result, Z-scores were used to summarize the interrelationships between LUSC and LUAD. Furthermore, we correlated network hub genes with patient survival time to identify risk factors.ResultsOur findings provided a look at the regulatory pattern for LUSC and LUAD. For LUSC, several genes, such as AKR1C1, AKR1C2, and AKR1C3, play key roles in regulating network modules of cell growth pathways. In addition, CCL19, CCR7, CCL21, and LY9 are enriched in LUAD network modules of T lymphocyte-related pathways. LUSC and LUAD have similar expressed gene expression patterns. Their networks share 46 hub genes with connectivity greater than 0.9. These genes are correlated with patient survival time. Among them, the expression level of COL5A2 in LUSC and LUAD is higher than that in normal tissues, which is closely related to the poor prognosis of LUSC and LUAD patients.ConclusionLUSC and LUAD share a network pattern. COL5A2 may be a risk factor in poor prognosis in LUSC and LUAD. The common landscape of LUSC and LUAD will help better define the regulation of NSCLC candidate genes and achieve the goals of precision medicine.

Background: Globally, non-small-cell lung cancer (NSCLC) has a high incidence, and NSCLC patients have poor prognoses. Lung squamous carcinoma (LUSC) is a major pathological type of NSCLC. LncRNAs play important roles in tumor progression and immune system functions. The aim of this study was to construct a predictive model with immune-related lncRNAs and to assess the immune microenvironment in middle- or advanced-stage LUSC patients. Methods: RNA sequencing data and corresponding clinical LUSC data were downloaded from The Cancer Genome Atlas. Immune genes were obtained from the Molecular Signatures Database. Immune-related lncRNAs were identified by Pearson correlation analysis in R. The model was constructed using univariate and multivariate Cox regression analyses. Finally, we validated the prognostic immune-related lncRNA model in a cohort from the Fudan University Shanghai Cancer Center. Results: Our risk model included four immune-related lncRNAs (LINC00944, AL034550.2, AC020907.1 and AC027682.6). Survival analysis revealed that overall and disease-free survival were shorter in the high-risk group than in the low-risk group. Independent prognostic analysis showed that our model could be used as an independent prognostic predictor. The high-risk group was positively associated with CD8+ T cells, B cells, myeloid dendritic cells, macrophages, regulatory T cells (Tregs) and cancer-associated fibroblasts and high expression of PD1 and CTLA4. Additionally, a low-risk score was correlated with lower half maximal inhibitory concentrations (IC50s) of cisplatin, docetaxel, vinorelbine and paclitaxel and a higher IC50 of gemcitabine. Gene set enrichment analysis suggested that these lncRNAs may participate in tumor progression and immune processes. Validation with the clinical cancer cohort demonstrated that higher risk scores were associated with a higher, but not statistically significant, likelihood of recurrence. Conclusion: We established a risk score model including four immune-related lncRNAs. The model accurately predicts the prognosis of middle- or advanced-stage LUSC patients and provides an important reference for individualized treatment.

Background: 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., Methods: The proportion of ALDH hi 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., Results: We found that hypoxia led to an increase in the proportion of ALDH hi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDH hi 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 ALDH hi 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., Conclusion: 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., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Clinical options for lung squamous carcinoma (LUSC) are still quite limited. Carcinogenesis is an exceedingly complicated process involving multi-level dysregulations. Therefore, only looking into one layer of genomic dysregulation is far from sufficient.Methods: We identified differentially expressed genes with consistent upstream genetic or epigenetic dysregulations in LUSC. Random walk was adopted to identify genes significantly affected by upstream abnormalities. Expression differentiation and survival analysis were conducted for these significant genes, respectively. Prognostic power of selected gene was also tested in 102 male LUSC samples through immunohistochemistry assay.Results: Twelve genes were successfully retrieved from biological network, including ERα (ESRS1), EGFR, AR, ATXN1, MAPK3, PRKACA, PRKCA, SMAD4, TP53, TRAF2, UBQLN4 and YWHAG, which were closely related to sex hormone signaling pathway. Survival analysis in public datasets indicated ERα was significantly associated with a poor overall survival (OS) in male LUSC. The result of our immunohistochemistry assay also demonstrated this correlation using R0 resected tumors (n = 102, HR: 2.152, 95% CI: 1.089-4.255, p = 0.024). Although disease-free survival (DFS) difference was non-significant (n = 102, p = 0.12), the tendency of distinction was straight-forward. Cox analysis indicated ERα was the only independent prognostic factor for male patients' OS after R0 resection (HR = 2.152, p = 0.037).Conclusion: ERα was significantly related to a poor prognosis in LUSC, especially for male patients after radical surgery, confirmed by our immunohistochemistry data. [ABSTRACT FROM AUTHOR]

Purpose: With the development and application of targeted therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), non-small cell lung cancer (NSCLC) patients have achieved remarkable survival benefits in recent years. However, epidermal growth factor receptor (EGFR) wild-type and low expression of programmed death-ligand 1 (PD-L1) NSCLCs remain unmanageable. Few treatments for these patients exist, and more side effects with combination therapies have been observed. We intended to generate a metabolic gene signature that could successfully identify high-risk patients and reveal its underlying molecular immunology characteristics. Methods: By identifying the bottom 50% PD-L1 expression level as PD-L1 low expression and removing EGFR mutant samples, a total of 640 lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) tumor samples and 93 adjacent non-tumor samples were finally extracted from The Cancer Genome Atlas (TCGA). We identified differentially expressed metabolic genes (DEMGs) by R package limma and the prognostic genes by Univariate Cox proportional hazards regression analyses. The intersect genes between DEMGs and prognostic genes were put into the least absolute shrinkage and selection operator (LASSO) penalty Cox regression analysis. The metabolic gene signature contained 18 metabolic genes generated and successfully stratified LUAD and LUSC patients into the high-risk and low-risk groups, which was also validated by the Gene Expression Omnibus (GEO) database. Its accuracy was proved by the time-dependent Receiver Operating Characteristic (ROC) curve, Principal Components Analysis (PCA), and nomogram. Furthermore, the Single-sample Gene Set Enrichment Analysis (ssGSEA) and diverse acknowledged methods include XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT-ABS, and CIBERSORT revealed its underlying antitumor immunosuppressive status. Besides, its relationship with somatic copy number alterations (SCNAs) and tumor mutational burden (TMB) was also discussed. Results: It is noteworthy that metabolism reprogramming is associated with the survival of the double-negative LUAD and LUSC patients. The SCNAs and TMB of critical metabolic genes can inhibit the antitumor immune process, which might be a promising therapeutic target. [ABSTRACT FROM AUTHOR]

PurposeWith the development and application of targeted therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), non-small cell lung cancer (NSCLC) patients have achieved remarkable survival benefits in recent years. However, epidermal growth factor receptor (EGFR) wild-type and low expression of programmed death-ligand 1 (PD-L1) NSCLCs remain unmanageable. Few treatments for these patients exist, and more side effects with combination therapies have been observed. We intended to generate a metabolic gene signature that could successfully identify high-risk patients and reveal its underlying molecular immunology characteristics.MethodsBy identifying the bottom 50% PD-L1 expression level as PD-L1 low expression and removing EGFR mutant samples, a total of 640 lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) tumor samples and 93 adjacent non-tumor samples were finally extracted from The Cancer Genome Atlas (TCGA). We identified differentially expressed metabolic genes (DEMGs) by R package limma and the prognostic genes by Univariate Cox proportional hazards regression analyses. The intersect genes between DEMGs and prognostic genes were put into the least absolute shrinkage and selection operator (LASSO) penalty Cox regression analysis. The metabolic gene signature contained 18 metabolic genes generated and successfully stratified LUAD and LUSC patients into the high-risk and low-risk groups, which was also validated by the Gene Expression Omnibus (GEO) database. Its accuracy was proved by the time-dependent Receiver Operating Characteristic (ROC) curve, Principal Components Analysis (PCA), and nomogram. Furthermore, the Single-sample Gene Set Enrichment Analysis (ssGSEA) and diverse acknowledged methods include XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT-ABS, and CIBERSORT revealed its underlying antitumor immunosuppressive status. Besides, its relationship with somatic copy number alterations (SCNAs) and tumor mutational burden (TMB) was also discussed.ResultsIt is noteworthy that metabolism reprogramming is associated with the survival of the double-negative LUAD and LUSC patients. The SCNAs and TMB of critical metabolic genes can inhibit the antitumor immune process, which might be a promising therapeutic target.

ROS1 rearrangements have been identified as driver mutations, accounting for 1–2% of lung adenocarcinoma, but are extremely rare in case of lung squamous cell carcinoma. In this work, we report a lung squamous cell carcinoma in a patient with peripheral lung cancer radiological manifestation, harboring ROS1 rearrangement, with high sensitivity to crizotinib. Our findings suggest that clinicians should pay more attention toward the occurrence of ROS1 rearrangements and the application of crizotinib for lung squamous cell carcinoma treatment.

ROS1 rearrangements have been identified as driver mutations, accounting for 1–2% of lung adenocarcinoma, but are extremely rare in case of lung squamous cell carcinoma. In this work, we report a lung squamous cell carcinoma in a patient with peripheral lung cancer radiological manifestation, harboring ROS1 rearrangement, with high sensitivity to crizotinib. Our findings suggest that clinicians should pay more attention toward the occurrence of ROS1 rearrangements and the application of crizotinib for lung squamous cell carcinoma treatment. [ABSTRACT FROM AUTHOR]

Abstract Emerging evidences demonstrate that circular RNAs (circRNAs) are abnormally expressed in tumors and could serve as prognostic markers for cancers. However, the expression patterns and clinical implications of circRNAs in non-small cell lung cancer (NSCLC) remain obscure. In this study, we profiled circRNA expressions in 10 pairs of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) after ribosomal RNA-depletion and RNase R digestion to enrich circRNAs. Combining five circRNA computational programs, we found that LUAD and LUSC not only share common expression patterns, but also exhibit distinct circRNA expression signatures. Moreover, the Receiver Operating Characteristic (ROC) curve analysis indicated that hsa_circ_0077837 and hsa_circ_0001821 could serve as potential biomarkers for both LUAD and LUSC, while hsa_circ_0001073 and hsa_circ_0001495 could be diagnostic/subtyping marker for LUAD and LUSC, respectively. Therefore, our findings highlight the important diagnostic potential of circRNAs in NSCLC.

There are associations between DNA methylation and the expression of long non-coding RNA (lncRNA), also known as lncRNA expression quantitative trait methylations (lnc-eQTMs). Lnc-eQTMs may induce a wide range of carcinogenesis pathways. However, lnc-eQTMs have not been globally identified and studied, and their roles in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) are largely unknown. In the present study, we identified some differential methylation sites located in genes of long intergenic non-coding RNAs (lincRNAs) and other types of lncRNAs in LUAD and LUSC. An integrated pipeline was established to construct two global cancer-specific regulatory networks of lnc-eQTMs in LUAD and LUSC. The associations between eQTMs showed common and specific features between LUAD and LUSC. Some lnc-eQTMs were also related with survival in LUAD- and LUSC-specific regulatory networks. Lnc-eQTMs were associated with cancer-related functions, such as lung epithelium development and vasculogenesis by functional analysis. Drug repurposing analysis revealed that these lnc-eQTMs may mediate the effects of some anesthesia-related drugs in LUAD and LUSC. In summary, the present study elucidates the roles of lnc-eQTMs in LUAD and LUSC, which could improve our understanding of lung cancer pathogenesis and facilitate treatment.

There are associations between DNA methylation and the expression of long non-coding RNA (lncRNA), also known as lncRNA expression quantitative trait methylations (lnc-eQTMs). Lnc-eQTMs may induce a wide range of carcinogenesis pathways. However, lnc-eQTMs have not been globally identified and studied, and their roles in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) are largely unknown. In the present study, we identified some differential methylation sites located in genes of long intergenic non-coding RNAs (lincRNAs) and other types of lncRNAs in LUAD and LUSC. An integrated pipeline was established to construct two global cancer-specific regulatory networks of lnc-eQTMs in LUAD and LUSC. The associations between eQTMs showed common and specific features between LUAD and LUSC. Some lnc-eQTMs were also related with survival in LUAD- and LUSC-specific regulatory networks. Lnc-eQTMs were associated with cancer-related functions, such as lung epithelium development and vasculogenesis by functional analysis. Drug repurposing analysis revealed that these lnc-eQTMs may mediate the effects of some anesthesia-related drugs in LUAD and LUSC. In summary, the present study elucidates the roles of lnc-eQTMs in LUAD and LUSC, which could improve our understanding of lung cancer pathogenesis and facilitate treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Peripheral monocyte count is an assessable parameter. Recently, evidence suggested an elevated preoperative monocyte counts predicting poor prognosis in malignancies. The aim of this study was to determine the prognostic effect of early postoperative blood monocyte count in patients with lung adenocarcinoma or squamous cell carcinoma following lobectomy. Methods We retrospectively reviewed patients with operated lung adenocarcinoma or squamous cell carcinoma from 2006 to 2011 in Western China Lung Cancer database. Univariate analysis on disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model. Results There were 433 patients enrolled in our analysis. High postoperative elevated monocyte was associated with male gender (P

Rationale and Objectives: To investigate whether iodine quantification extracted from enhanced dual energy-computed tomography (DE-CT) is useful for distinguishing lung squamous cell carcinoma from adenocarcinoma and to evaluate whether a single scan evaluated during the venous phase (VP) can be substituted for scans evaluated during other phases.Materials and Methods: Sixty-two patients with lung cancer (32 squamous cell carcinomas; 30 adenocarcinomas) underwent enhanced dual-phase DE-CT scans, including an arterial phase and VP. The iodine concentration (IC), normalized iodine concentration (NIC), and slope of the curve (K) in lesions were measured during two scanning phases in two different pathological types of lung cancers. The differences in parameters (IC, NIC, and K) between these two types of lung cancers were statistically analyzed. In addition, the receiver operating characteristic curves of these parameters were performed to discriminate squamous cell carcinoma from adenocarcinoma.Results: The mean IC, NIC, and K in adenocarcinomas were all higher than those in squamous cell carcinomas during the two scanning phases. However, the differences in these parameters between the two types of cancers were significant only during the VP, not during the arterial phase. Receiver operating characteristic analysis demonstrated that the optimal thresholds of the IC, NIC, and K for discriminating squamous cell carcinoma from adenocarcinoma were 1.550, 0.227, and 1.608, respectively. In addition, the sensitivity, specificity, and area under the curve were 81.2%, 83.3%, and 0.871 for the IC; 56.2%, 93.3%, and 0.800 for the NIC; and 65.6%, 80%, and 0.720 for the K; 81.3%, 83.3%, and 0.874 for the IC + NIC; 68.8%, 93.3%, and 0.891 for the IC + NIC + K, respectively. The "IC + NIC + K" had the highest diagnostic efficiency for discriminating two types of lung cancers, but with low sensitivity. Whereas, "IC"and "IC + NIC" had the similar lower diagnostic efficiency, but with high sensitivity and specificity.Conclusion: The iodine quantification parameters derived from enhanced DE-CT during the VP may be useful for distinguishing lung squamous cell carcinoma from adenocarcinoma. [ABSTRACT FROM AUTHOR]

Lung cancer with highest morbidity and mortality seriously threatens human health worldwide. Long noncoding RNAs (lncRNAs) exert important biological functions by acting as microRNA, which is implicated in tumorigenesis and cancer development. Previous work has reported that lncRNA-ATB expression was significantly upregulated in lung adenocarcinoma tissues and promoted tumor progression; however, the mechanisms of lncRNA-ATB in lung squamous carcinoma (LSC) are still fairly elusive. In our study, lncRNA-ATB expression also markedly increases in LSC tissues and cell lines in comparison to the adjacent normal tissues and normal lung epithelial cells, respectively. Functional experiments indicate that lncRNA-ATB overexpression improves the proliferative, migratory, and invasive capabilities of normal lung epithelial cells compared with control group. Furthermore, the migratory and invasive abilities are strikingly inhibited in lncRNA-ATB silenced LSC cells. Mechanistically, lncRNA-ATB directly binds to microRNA-590-5p and downregulates microRNA-590-5p level, leading to the upregulation of NF-90 expression. In addition, lncRNA-ATB overexpression promotes the epithelial–mesenchymal transition process, where lncRNA-ATB overexpression facilitates the expression of mesenchymal phenotype related molecules N-cadherin and vimentin, while restrains the expression of epithelial phenotype related proteins E-cadherin and CK-19, compared to the control. Conversely, microRNA-590-5p mimics can reverse the results caused by lncRNA-ATB overexpression. Taken together, our initial data suggest that lncRNA-ATB overexpression may promote the progression of LSC by modulating the microRNA-590-5p/NF-90 axis. [ABSTRACT FROM AUTHOR]

FAM13A is associated with aging lung disease (primarily chronic obstructive pulmonary disorder and pulmonary fibrosis) and shows stable expression throughout lung development. However, a few systematic studies of FAM13A have been conducted to assess the pathogenesis of lung cancer, particularly susceptibility. We predicted that single-nucleotide polymorphisms (SNPs) in FAM13A may be associated with lung cancer development. We systematically selected five functional SNPs (rs2602120, rs3017895, rs9224, rs7657817, and rs3756050) and genotyped them with the Genesky proprietary improved Multiligase Detection Reaction multiplex SNP genotyping system in a case-control study of 626 lung cancer cases and 667 cancer-free controls. The functional effects of FAM13A and specific miRNAs (miRNA-22-5p and miRNA-1301-3p) were evaluated based on The Cancer Genome Atlas database. We found that rs9224 in the 3′ untranslated region (UTR) of FAM13A was potentially associated with an increased risk of lung squamous carcinoma (LUSQ) (additive model: odds ratio = 1.47, 95% confidence interval = 1.04–2.07, p = 0.028). In addition, the results of expression quantitative trait loci analysis suggested that the rs9224 polymorphism affects the expression of FAM13A (p = 0.050) and miRNA-22-5p (p = 0.031) in LUSQ. Further, survival analysis indicated decreased overall survival in the presence of the variant alleles of rs9224 (p = 0.048). The present results indicate that variant genotypes of rs9224 in the FAM13A 3′UTR may modify LUSQ susceptibility by affecting the binding of miRNA-22-5p and predict a poor prognosis of patients with LUSQ. [ABSTRACT FROM AUTHOR]

OTUD7B, a multifunctional deubiquitinylase, plays an essential role in inflammation and proliferation signals. However, its function in lung cancer remains largely unknown. The aim of this study was to evaluate the prognostic significance of OTUD7B in patients with lung adenocarcinoma and squamous carcinoma and to characterize its molecular mechanisms in lung cancer progression and metastasis. Two tissue microarrays containing 150 pairs of lung squamous carcinoma and matched adjacent non-cancer tissues, and one tissue microarray containing 75 pairs of lung adenocarcinoma and adjacent non-cancer tissues were included, and immunohistochemical staining was performed to assess the clinical relevance of OTUD7B in non-small cell lung cancer. OTUD7B is highly expressed in both lung squamous carcinoma and adenocarcinoma and correlates with a worse prognosis. MTT proliferation, colony formation, migration and invasion assays and immunoblotting assay in NCI-H358 and A549 cell lines suggested that OTUD7B enhances EGF-induced Akt signal transduction and promotes lung cancer cell proliferation and migration. Immunohistochemical staining of large-scale lung cancer subjects (171 cases) revealed positive correlation of OTUD7B and VEGF expression. ELISA and tube formation assay revealed OTUD7B promotes VEGF production and angiogenesis. NCI-H358 tumor model demonstrated OTUD7B is required for lung tumor progression by facilitating activation of Akt signaling. These findings collectively identified OTUD7B as an independent predictive factor for the prognosis of non-small cell lung cancer and revealed OTUD7B promotes lung cancer cell proliferation and metastasis via Akt/VEGF signal pathway.

OTUD7B, a multifunctional deubiquitinylase, plays an essential role in inflammation and proliferation signals. However, its function in lung cancer remains largely unknown. The aim of this study was to evaluate the prognostic significance of OTUD7B in patients with lung adenocarcinoma and squamous carcinoma and to characterize its molecular mechanisms in lung cancer progression and metastasis. Two tissue microarrays containing 150 pairs of lung squamous carcinoma and matched adjacent non-cancer tissues, and one tissue microarray containing 75 pairs of lung adenocarcinoma and adjacent non-cancer tissues were included, and immunohistochemical staining was performed to assess the clinical relevance of OTUD7B in non-small cell lung cancer. OTUD7B is highly expressed in both lung squamous carcinoma and adenocarcinoma and correlates with a worse prognosis. MTT proliferation, colony formation, migration and invasion assays and immunoblotting assay in NCI-H358 and A549 cell lines suggested that OTUD7B enhances EGF-induced Akt signal transduction and promotes lung cancer cell proliferation and migration. Immunohistochemical staining of large-scale lung cancer subjects (171 cases) revealed positive correlation of OTUD7B and VEGF expression. ELISA and tube formation assay revealed OTUD7B promotes VEGF production and angiogenesis. NCI-H358 tumor model demonstrated OTUD7B is required for lung tumor progression by facilitating activation of Akt signaling. These findings collectively identified OTUD7B as an independent predictive factor for the prognosis of non-small cell lung cancer and revealed OTUD7B promotes lung cancer cell proliferation and metastasis via Akt/VEGF signal pathway. [ABSTRACT FROM AUTHOR]

Abstract Interleukin (IL)-7 enhances cytokines secretion by CD14+ monocytes, and induces recruitment of monocytes to endothelium. As an important regulator to different types of immune cells, the role of IL-7 in modulation of CD14+ monocytes is still not fully elucidated. Thus, the aim of current study was to investigate the immunoregulatory activity of IL-7 to peripheral and lung-resident CD14+ monocytes in lung squamous carcinoma patients. Thirty-seven lung squamous carcinoma patients and eighteen healthy individuals were enrolled. CD14+ monocytes and CD4+ T cells were purified from both peripheral bloods and bronchoalveolar lavage fluids (BALF). IL-7 expression in plasma and BALF was measured by ELISA, and CD127 expression in peripheral and lung-resident CD14+ monocytes was investigated by real-time PCR and flow cytometry, respectively. Cellular proliferation, cytokine production, and molecules in IL-7 signaling pathway was assessed in CD14+ monocytes in response to IL-7 stimulation. IL-7-induced CD14+ monocytes activity to CD4+ T cells was also assessed in direct and indirect contact co-culture system. There were no remarkable differences of plasma IL-7 concentration or CD127 level between healthy individuals and lung squamous carcinoma patients. However, IL-7 expression was significantly reduced in BALF from tumor site in squamous carcinoma patients, especially in stage III and IV. IL-7 stimulation not only promoted proliferation, cytokines secretion, and STAT-5 phosphorylation in lung-resident CD14+ monocytes, but also enhanced CD14+ monocytes-induced Th1 and T follicular helper cells activation, which presented as elevated interferon-γ and IL-21 secretion by CD4+ T cells. This process required direct cell-to-cell contact, and was dependent on IL-6 secretion. The current data revealed a potential immunopromotive property of IL-7 to lung-resident CD14+ monocytes in lung squamous carcinoma. Highlights • IL-7 level was reduced in BALF from tumor site in lung squamous carcinoma patients. • IL-7 promoted proliferation and cytokines secretion of lung-resident CD14+ monocytes. • IL-7 enhanced lung-resident CD14+ monocytes-induced CD4+ T cells activation. • CD14+ monocytes-induced CD4+ T cells activation required direct contact and IL-6 secretion. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) is often diagnosed at the advanced stage with poor prognosis. The mechanisms of its pathogenesis and prognosis require urgent elucidation. This study was performed to screen potential biomarkers related to the occurrence, development and prognosis of LUSC to reveal unknown physiological and pathological processes. Using bioinformatics analysis, the lung squamous cell carcinoma microarray datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were analyzed to identify differentially expressed genes (DEGs). Furthermore, PPI and WGCNA network analysis were integrated to identify the key genes closely related to the process of LUSC development. In addition, survival analysis was performed to achieve a prognostic model that accomplished good prediction accuracy. Three hundred and thirty–seven up–regulated and 119 down-regulated genes were identified, in which four genes have been found to play vital roles in LUSC development, namely CCNA2, AURKA, AURKB, and FEN1. The prognostic model contained 5 genes, which were all detrimental to prognosis. The AUC of the established prognostic model for predicting the survival of patients at 1, 3, and 5 years was 0.692, 0.722, and 0.651 in the test data, respectively. In conclusion, this study identified several biomarkers of significant interest for additional investigation of the therapies and methods of prognosis of lung squamous cell carcinoma.

Background  The purpose of our study was to construct a prognostic model based on ferroptosis-related gene signature to improve the prognosis prediction of lung squamous carcinoma (LUSC). Methods  The mRNA expression profiles and clinical data of LUSC patients were downloaded. LUSC-related essential differentially expressed genes were integrated for further analysis. Prognostic gene signatures were identified through random forest regression and univariate Cox regression analyses for constructing a prognostic model. Finally, in a preliminary experiment, we used the reverse transcription-quantitative polymerase chain reaction assay to verify the relationship between the expression of three prognostic gene features and ferroptosis. Results  Fifty-six ferroptosis-related essential genes were identified by using integrated analysis. Among these, three prognostic gene signatures (HELLS, POLR2H, and POLE2) were identified, which were positively affected by LUSC prognosis but negatively affected by immune cell infiltration. Significant overexpression of immune checkpoint genes occurred in the high-risk group. In preliminary experiments, we confirmed that the occurrence of ferroptosis can reduce three prognostic gene signature expression. Conclusions  The three ferroptosis-related genes could predict the LUSC prognostic risk of antitumor immunity., Competing Interests: Conflicts of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Peripheral monocyte count is an assessable parameter. Recently, evidence suggested an elevated preoperative monocyte counts predicting poor prognosis in malignancies. The aim of this study was to determine the prognostic effect of early postoperative blood monocyte count in patients with lung adenocarcinoma or squamous cell carcinoma following lobectomy.Methods: We retrospectively reviewed patients with operated lung adenocarcinoma or squamous cell carcinoma from 2006 to 2011 in Western China Lung Cancer database. Univariate analysis on disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model.Results: There were 433 patients enrolled in our analysis. High postoperative elevated monocyte was associated with male gender (P < 0.001), positive smoking history (P = 0.005), and higher N stage (P = 0.002) and higher tumor stage (P = 0.026). Two-tailed log-rank test indicated patients with an early postoperative elevated monocyte count predicted a poor DFS and OS overall (P < 0.001, P < 0.001, respectively) as well as in subgroup analysis, and further presented as a promising independent prognostic factor for both DFS and OS (HR = 2.991, 95%CI: 2.243-3.988, P < 0.001; HR = 2.705, 95%CI: 1.977-3.700, P < 0.001, respectively) on multivariate analysis. However, no significance was detected for preoperative monocyte in multivariate analysis.Conclusions: Elevated early postoperative peripheral monocyte count was an independent prognostic factor of poor prognosis and inferior clinicopathological features for patients with operable lung adenocarcinoma or squamous cell carcinoma by lobectomy. [ABSTRACT FROM AUTHOR]