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Previous studies have suggested increased activity of phosphatidylethanolamine binding protein 4 (PEBP4) may be associated with the prognosis of non-small cell lung cancer. However, to the best of our knowledge, no direct association between PEBP4 and lung squamous cell carcinoma (LSCC) has been reported. In the present study, a systematic review and meta-analysis was performed to examine the gene expression activity of PEBP4 in LSCC. A total of 10 out of 131 gene expression datasets from the Gene Expression Omnibus (GEO) were selected, including 574 samples (319 patients with LSCC and 255 healthy controls). Subsequently, multiple linear regression (MLR) was employed to study three potential influencing factors: Sample size, population region and study date. A literature-based pathway analysis was then conducted to examine the potential mechanisms through which PEBP4 may exert influence on LSCC. The results of a meta-analysis indicated that, in LSCC, PEBP4 exhibited significantly low expression levels (P<0.033), with mildly increased gene expression levels observed in three studies (log fold-change: 0.072-2.13). However, a significant between-study variance was observed from the heterogeneity analysis. MLR indicated that population region was a significant factor (P<0.0065), whereas sample size and study age were not (P>0.46). Eight functional pathways were subsequently identified, through which PEBP4 may influence the prognosis of LSCC and its response to treatment. The results of the present study suggested that the effects of PEBP4 on LSCC can be neglected in most cases of LSCC, where PEBP4 demonstrated decreased expression levels. However, in the case of PEBP4 overexpression, it may contribute to the progression of LSCC and lead to the development of drug resistance. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) progression is accompanied by changes in protein levels that may be reflected in body fluids, such as plasma, bronchoalveolar lavage fluid (BALF) and urine. Certain proteins present in these biofluids can facilitate lung cancer diagnosis. Kininogen 1 (KNG1), osteopontin (OPN) and α-1-antitrypsin (AAT) are associated with tumorigenesis. The present study aimed to explore the combined monitoring of plasma, urine and BALF to gain insight into LUSC by monitoring the levels of the above three protein using ELISA. LUSC (n=31) and healthy controls with benign lung diseases (n=20) were enrolled in the study. KNG1 levels in plasma, BALF and urine were significantly higher in patients with LUSC patients than in controls (P<0.0001, P<0.0001 and P=0.0010, respectively). OPN was upregulated in the plasma and BALF of patients with LUSC relative to controls (P=0.0107 and P=0.0004, respectively), whereas its levels in the urine of healthy controls were significantly higher (P=0.0088). Patients with LUSC had higher AAT levels in plasma, BALF and urine compared with those of the controls (P=0.0022, P=0.0014 and P=0.0005, respectively). Receiver operating characteristic analysis showed an area under the curve (AUC) of 0.81 for KNG1 in plasma, 0.91 in BALF and 0.81 in urine. The AUC for OPN was 0.71 in plasma, 0.83 in BALF and 0.75 in urine. The AUC for AAT was 0.74 in plasma, 0.74 in BALF and 0.86 in urine. Immunohistochemical staining in 20 paired LUSC and adjacent normal tissues showed that KNG1, OPN and AAT levels were higher in LUSC tissues. Therefore, our results showed that KNG1, OPN and AAT in biofluids might be useful for the diagnosis of LUSC. These markers in urine and BALF may be better than in plasma for detecting LUSC. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylations have been reported to be significantly associated with lung squamous cell cancer (LUSC). The aim of this study was to investigate the DNA methylation-driven genes in LUSC by integrative bioinformatics analysis. In the present study, methylation-driven genes in LUSC were screened out, and survival analysis related to these genes was performed to confirm their value in prognostic assessment. Gene expression and methylation data were downloaded from The Cancer Genome Atlas (TCGA), and the MethylMix algorithm was used to identify methylation-driven genes. ConsensusPathDB was used to perform Gene Ontology and pathway enrichment analysis of methylation-driven genes. Survival analysis was performed to investigate the correlation with prognosis. In total, 52 differentially expressed methylation-driven genes were identified in LUSC and adjacent tissues. Survival analysis showed that DQX1, GPR75, STX12, and TRIM61 could serve as independent prognostic biomarkers. In addition, the combined methylation and gene expression survival analysis revealed that the combined expression level of the genes ALG1L, DQX1, and ZNF418 alone can be used as a prognostic marker or drug target. Methylation of four sites of gene ZNF418, four sites of ZNF701, two sites of DQX1, and four sites of DCAF4L2 was significantly associated with survival. The present study provides an important bioinformatic and relevant theoretical basis for subsequent early diagnosis and prognostic assessment of LUSC. [ABSTRACT FROM AUTHOR]

The discovery of lung carcinoma subtype-specific gene expression changes has the potential to elucidate the molecular differences and provide personalized therapeutic targets for these pathologies. The aim of the present study was to characterize the genetic profiles of the early stages (IA/IB) of two non-small cell lung cancer subtypes, adenocarcinoma (AD) and squamous cell carcinoma (SC). RNA-Seq gene expression data from The Cancer Genome Atlas was analyzed to compare the gene expression differences between AD and SC. The gene sets specific to each subtype were further analyzed to identify the enriched Gene Ontology terms, Kyoto Encyclopedia of Genes and Genomes pathways and biological functions. The results demonstrated that a unique set of genes (145 upregulated and 27 downregulated) was altered in AD, but not in SC; another set of genes (146 upregulated and 103 downregulated) was significantly altered in SC, but not in AD. Genes highly upregulated specifically in AD included albumin (1,732-fold), protein lin-28 homolog A, which is a positive regulator of cyclin-dependent kinase 2 (150-fold) and gastric lipase (81-fold). Genes highly upregulated specifically in SC included amelotin (618-fold), alcohol dehydrogenase 7 (57-fold), aclerosteosis (55-fold) and claudin-22 (54-fold). Several cancer/testis antigen family genes were notably upregulated in SC, but not in AD, whereas mucins were upregulated only in AD. Functional pathway analysis demonstrated that the dysregulation of genes associated with retinoid X receptors was common in AD and SC, genes associated with 'lipid metabolism' and 'drug metabolism' were dysregulated only in SC, whereas genes associated with 'molecular transport' and 'cellular growth and proliferation' were significantly enriched in AD specifically. These results reveal fundamental differences in the gene expression profiles of early-stage AD and SC. In addition, the present study identified molecular pathways that are uniquely associated with the pathogenesis of these subtypes. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related mortality worldwide. Despite progress in the treatment of non-small-cell lung cancer, there are limited treatment options for lung squamous cell carcinoma (LUSC), compared with lung adenocarcinoma. The present study investigated the disease mechanism of LUSC in order to identify key candidate genes for diagnosis and therapy. A total of three gene expression profiles (GSE19188, GSE21933 and GSE74706) were analyzed using GEO2R to identify common differentially expressed genes (DEGs). The DEGs were then investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. A protein-protein interaction (PPI) network was constructed via the Search Tool for the Retrieval of Interacting Genes/Proteins, and visualized using Cytoscape software. The expression levels of the hub genes identified using CytoHubba were validated using the University of California, Santa Cruz (UCSC) database and the Human Protein Atlas. A Kaplan-Meier curve and Gene Expression Profiling Interactive Analysis were then employed to evaluate the associated prognosis and clinical pathological stage of the hub genes. Furthermore, non-coding RNA regulatory networks were constructed using the Gene-Cloud Biotechnology information website. A total of 359 common DEGs (155 upregulated and 204 downregulated) were identified, which were predominantly enriched in 'mitotic nuclear division', 'cell division', 'cell cycle' and 'p53 signaling pathway'. The PPI network consisted of 257 nodes and 2,772 edges, and the most significant module consisted of 66 upregulated genes. A total of 19 hub genes exhibited elevated RNA levels, and 10 hub genes had elevated protein levels compared with normal lung tissues. The upregulation of five hub genes (CCNB1, CEP55, FOXM1, MKI67 and TYMS; defined in Table I) were significantly associated with poor overall survival and unfavorable clinical pathological stages. Various ncRNAs, such as C1orf220, LINC01561 and MGC39584, may also play important roles in hub-gene regulation. In conclusion, the present study provides further understanding of the pathogenesis of LUSC, and reveals CCNB1, CEP55, FOXM1, MKI67 and TYMS as potential biomarkers or therapeutic targets. [ABSTRACT FROM AUTHOR]

The high mortality rate of lung squamous cell carcinoma (LUSC) is in part due to the lack of early detection of its biomarkers. The identification of key molecules involved in LUSC is therefore required to improve clinical diagnosis and treatment outcomes. The present study used the microarray datasets GSE31552, GSE6044 and GSE12428 from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted to construct the protein-protein interaction network of DEGs and hub genes module using STRING and Cytoscape. The 67 DEGs identified consisted of 42 upregulated genes and 25 downregulated genes. The pathways predicted by KEGG and GO enrichment analyses of DEGs mainly included cell cycle, cell proliferation, glycolysis or gluconeogenesis, and tetrahydrofolate metabolic process. Further analysis of the University of California Santa Cruz and ONCOMINE databases identified 17 hub genes. Overall, the present study demonstrated hub genes that were closely associated with clinical tissue samples of LUSC, and identified TYMS, CCNB2 and RFC4 as potential novel biomarkers of LUSC. The findings of the present study contribute to an improved understanding of the molecular mechanisms of carcinogenesis and progression of LUSC, and assist with the identification of potential diagnostic and therapeutic targets of LUSC. [ABSTRACT FROM AUTHOR]

Lung cancer has high incidence and mortality rates, and lung squamous cell carcinoma (LUSC) is a common form of non-small-cell lung carcinoma (NSCLC). The aim of our study was to discover long non-coding RNAs (lncRNAs) associated with LUSC prognosis. RNA-sequencing data obtained from LUSC samples were extracted from The Cancer Genome Atlas database. Using the limma package, differentially expressed genes (DEGs; including differentially expressed lncRNA genes (DELs), coding genes (DECs), and other genes (DEOs)) between LUSC and control samples were analyzed. Using Kaplan-Meier survival analysis, prognosis-associated lncRNAs were further selected. Following the calculation of Pearson's correlation coefficients between DELs and other DEGs, the DEL-DEG co-expression network was visualized using Cytoscape software. Using the clusterProfiler package, potential functions for DECs co-expressed with DELs were predicted. There were 1,305 DEGs in LUSC samples, including 153 DELs, 1,109 DECs, and 43 DEOs. Based on survival analysis, 22 prognosis-associated lncRNAs (including surfactant associated 1, pseudogene (SFTA1P), long intergenic non-protein coding RNA 968 (LINC00968), GATA6 antisense RNA 1, (GATA6-AS1) TBX5 antisense RNA 1 (TBX5-AS1) and FEZF1 antisense RNA 1 (FEZF1-AS1)) in LUSC were selected from these DELs, and the associated abnormal expression levels were also verified in LUSC clinical samples. A DEL-DEG co-expression network was constructed, which involved 93 DELs. Co-expressed DECs were enriched for only 8 prognosis-associated DELs, including LINC00968, SFTA1P, and TBX5-AS1. Specifically, mitogen-activated protein kinase (MAPK) signaling pathway-associated genes were enriched in DECs co-expressed with LINC00968, SFTA1P, GATA6-AS1, TBX5-AS1 and FEZF1-AS1, which may be prognosis-associated lncRNAs in LUSC. In addition, LINC00968 may affect the outcome of patients with LUSC via the MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LSCC) exhibits a number of similarities with lung adenocarcinoma (LA) in terms of copy number alterations. However, compared with LA, the range of genetic alterations in LSCC is less understood. In the present study, a large-scale literature-based search of LA-associated genes and LSCC-associated genes was performed to identify the genetic basis in common with these two diseases. For each of the LA-associated genes, a mega-analysis was performed to test its expression variations in LSCC using 11 RNA expression datasets, with significant genes identified using statistical analysis. Subsequently, a functional pathway analysis was performed to identify a possible association between any of the significant genes identified from the mega-analysis and LSCC, followed by a co-expression analysis. A multiple linear regression (MLR) model was employed to investigate the possible influence of sample size, country of origin and study date on gene expression in patients with LSCC. Disease-gene association data analysis identified 1,178 genes involved in LA, 334 in LSCC, with a significant overlap of 187 genes (P<1.02×−161). Mega-analysis revealed that three LA-associated genes, such as solute carrier family 2 member 1 (SLC2A1), endothelial PAS domain protein 1 (EPAS1) and cyclin-dependent kinase 4 (CDK4), were significantly associated with LSCC (P<1.60×10−8), with multiple potential pathways identified by functional pathway analysis, which were further validated by co-expression analysis. The present MLR analysis suggested that the country of origin was a significant factor for the levels of expression of all three genes in patients with LSCC (P<4.0×10−3). Collectively, the present results suggested that genes associated with LA should be further investigated for their association with LSCC. In addition, SLC2A1, EPAS1 and CDK4 may be novel risk genes associated with LA and LSCC. [ABSTRACT FROM AUTHOR]

Natural dietary components have become the subject of an increasing amount of interest due to the side effects of anticancer treatment. Pterostilbene, an analog of resveratrol, is primarily found in grapes, and has been suggested to exert antioxidant and anticancer effects in different tumor types. The present study aimed to investigate the antitumor effects and molecular mechanisms of pterostilbene in the human lung squamous cell carcinoma (SqCC) cell line, H520. The results of the present study indicate that pterostilbene significantly reduced cell viability and induced S phase arrest, and that treatment with pterostilbene was associated with the downregulation of cyclin A and cyclin E, as with the upregulation of p21 and p27 expression in H520 cells. In the apoptosis analysis, pterostilbene induced S phase accumulation and the activation of caspase-3, −8 and −9 in H520 cells, potentially through the activation of extrinsic and intrinsic apoptotic pathways. Additionally, the in vivo study demonstrated that pterostilbene effectively inhibited lung SqCC growth in a H520 ×enograft model. Given the in vitro and in vivo antitumor effects of pterostilbene demonstrated in the present study, pterostilbene may serve a novel and effective therapeutic agent to for patients with SqCC. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify potential molecular markers of lung squamous cell carcinoma (LUSC). Three datasets containing LUSC mRNA sequencing data were downloaded from the Gene Expression Omnibus, The Cancer Genome Atlas and the Gene Expression Profiling Interactive Analysis databases. These datasets were used to identify significantly differentially expressed genes (DEGs) in LUSC. A protein-protein interaction network of the DEGs was constructed followed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and overall survival analyses of the DEGs. A total of 37 DEGs between LUSC and normal tissues were identified, including 26 downregulated genes and 11 upregulated genes. Biological Process enrichment analysis revealed that the DEGs were mainly enriched in 'cell adhesion', 'cell-matrix adhesion', 'anatomical structure morphogenesis', 'ECM-receptor interaction' and 'focal adhesion'. Overall survival analysis demonstrated that transcription factor 21, α-2-macroglobulin, acyl-CoA synthetase long chain family member 5, integrin subunit β8, meiotic nuclear divisions 1 and secretoglobin family 1A member 1 were significantly associated with the occurrence and development of lung cancer, and these genes were selected as hub genes. The results obtained in the present study may aid the elucidation of the molecular mechanisms involved in the development of LUSC and may provide potential targets for LUSC treatment. [ABSTRACT FROM AUTHOR]

There have been hundreds of genes demonstrated to be associated with lung squamous cell carcinoma (LSCC), presenting various degrees of association with this disease. In the present study, gene vectors were investigated as genetic biomarkers for the diagnosis and personalized treatment of LSCC. A LSCC genetic database (LSCC_GD) was developed through literature‑associated data analysis, where 260 LSCC target genes were curated. Subsequently, numerous associations between these genes and LSCC were studied. Following this, a sparse representation‑based variable selection (SRVS) was employed for gene selection from two LSCC gene expression datasets, followed by a case/control classification. Results were compared using analysis of variance (ANOVA)‑based gene selection approaches. Using SRVS, a gene vector was selected from each dataset, resulting in significantly higher classification accuracy (CR), compared with randomly selected genes (For datasets GSE18842 and GSE1987, CR=100 and 100% and permutation P=5.0x10‑4 and 1.8x10‑3, respectively). The SRVS method outperformed ANOVA in terms of the classification ratio. The results indicated that, for a given dataset, there may be a gene vector from the 260 curated LSCC genes that possesses significant prediction power. SRVS is effective in identifying the optimum gene subset target for personalized treatment. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the two major subtypes of lung cancer. To explore mitochondrial respiratory gene expression profiles in LUSC and LUAD, RNA sequencing data from The Cancer Genome Atlas was used for comprehensive analyses to establish the molecular characteristics of LUSC and LUAD. To elucidate expression profiles, subtypes were defined using unsupervised clustering of mitochondrial gene expression data. Differences in nuclear gene expression levels, signaling pathways and tumor microenvironments between subtypes were investigated. The analysis revealed that mitochondrial respiratory genes were generally expressed at lower levels in tumor tissues compared with matched control tissues. The expression of mitochondrially encoded NADH dehydrogenase 5 or 6 was associated with tumor progression in LUAD and LUSC. Patients were clustered into three subgroups based on the expression profile of 13 mitochondrial protein‑encoding genes, and patients in Cluster 3 exhibited poor survival rates compared with patients from Cluster 1. Furthermore, this association was also observed in another independent data set. Further analyses of the expression of nuclear‑encoded genes in the three clusters revealed the enrichment of several cancer‑associated signaling pathways in Cluster 3, particularly the apoptotic signaling pathway, suggesting a potential association between the decreased expression of mitochondrial DNA genes and increased tumor aggressiveness. Furthermore, the analyses of immune cell compositions in the tumor microenvironment detected a significant increase in the proportion of CD4+ T cells and a decrease in the proportion of macrophages in LUAD compared with LUSC (P=0.0000104 and P=0.0000105, respectively). In conclusion, the present study revealed an association between the expression patterns of mitochondrial‑encoded genes and lung cancer, which may contribute to novel therapeutic strategies for patients with LUSC and LUAD. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that the interleukin (IL)‑6/ IL‑6 receptor (IL‑6R) signaling pathway contributes to the pathogenesis of lung cancer. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two major pathological subtypes of non‑small cell lung cancer (NSCLC). The present study aimed to elucidate the potential clinical prognosis and biological function of IL‑6R mRNA expression in LUAD and LUSC. The search term ‘lung cancer’ was used to search through the Gene Expression Omnibus database. Including LUAD and LUSC datasets in The Cancer Genome Atlas database, a total of 8 LUAD and 6 LUSC datasets were included in the present analysis. It was observed that a higher expression level of IL‑6R mRNA in tumor tissues was a significant positive prognostic factor for overall survival in LUAD [pooled hazard ratio (HR), 0.48 and P<0.001 for univariate analysis; pooled HR, 0.50 and P<0.001 for multivariate analysis] while there was no similar association in LUSC (pooled HR, 1.59 and P=0.062 for univariate analysis; pooled HR, 1.58 and P=0.079 for multivariate analysis). Correlation analysis revealed that IL‑6 and IL‑6R were negatively correlated in LUAD and positively correlated in LUSC. IL‑6R and its most correlated genes were primarily involved in cell cycle progression in LUAD and primarily involved in tumor angiogenesis, invasion and metastasis in LUSC. These results suggest a possible role of tumoral expression for IL‑6R in LUAD, which means it may have potential as a prognostic marker for this type of cancer. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor involved in cell proliferation and apoptosis, which is highly expressed in lung squamous cell carcinoma (SCC). The present study aimed to observe the influence of IGF-1R silencing on the radiosensitivity of SCC and investigate the potential mechanisms involved. Human lung SCC H520 cells with relatively high expression of IGF-1R were used. IGF-1R expression was silenced using short hairpin RNA. The influence of IGF-1R silencing on radiosensitivity and apoptosis was assessed using a clone formation assay and flow cytometry. The expression levels of proteins relevant in DNA damage repair and hypoxic signaling pathways were analyzed using western blotting. Decreased expression of IGF-1R led to an increase in the sensitivity of H520 cells to irradiation. Molecular analysis showed that the reduced expression of IGF-1R decreased the protein expression of ataxia-telangiectasia mutated (ATM), H2A histone family member X (H2AX) and p53 binding protein 1 (53BP1), which are associated with the DNA repair pathway. Furthermore, 53BP1 is also known to be involved in apoptosis. Proteins involved in the hypoxic pathway, including hypoxia inducible factor 1 α (HIF-1α), matrix metallopeptidase 9 (MMP-9) and vascular endothelial growth factor A (VEGFA) were also involved in the radiosensitivity. In conclusion, decreased expression of IGF-1R leads to improved radiosensitivity of SCC cells, and the underlying mechanism may be associated with the decreased expression of proteins involved in ATM/H2AX/53BP1 DNA damage repair and the HIF-1α/MMP-9 hypoxic pathway, which results in the induction of apoptosis and increased radiosensitivity. These findings suggest that targeting of IGF-1R may represent a novel approach for lung SCC radiation treatment. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LSCC), the second most common type of lung cancer, has received limited attention. Patient‑derived tumor xenografts (PDTXs) are useful preclinical models to reproduce the diverse heterogeneity of cancer, but it is important to identify potential variations during their establishment. A total of 18 PDTXs were established from 37 the surgical specimens and 16 were serially passaged to third generation. Second‑ and third‑generation xenografts had a faster growth rate in mice. The tumor implantation success rate was associated with poorer differentiation, larger tumor volume and higher expression of Ki‑67. The xenografts largely retained histological and key immunophenotypic features (including p53, p63, cytokeratin5/6, and E‑cadherin). However, increased Ki‑67 expression was identified in partial xenografts. Long non‑coding RNA (lncRNA) and mRNA expression in third‑generation xenografts differed from that of matched primary tumors. Gene Ontology and pathway analysis showed that mRNAs involved in cell cycle, and metabolism regulation were generally upregulated in xenografts, while those associated with immune responses were typically downregulated. Furthermore, the responses of xenografts to cisplatin were consistent with clinical outcome. In the present study, PDTXs of SCC were successfully established, and closely resembled their original tumor regarding their immunophenotype and response to cisplatin. Overall, PDTXS of LSCC altered the lncRNA profile and increased the proliferative activity of cancer cells, whilst retaining responsiveness to cisplatin. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) is the second major type of lung cancer globally. The majority of patients with LUSC are clinically diagnosed at the advanced stages, thus it is urgent to identify suitable prognostic markers for LUSC. B-cell lymphoma 2 (Bcl-2) has been widely studied in non-small cell lung cancer (NSCLC). However, the prognostic role of Bcl-2 in NSCLC remains conflicting and controversial, particularly for LUSC. Although certain studies have been performed to identify the prognostic value of Bcl-2, to the best of our knowledge, no study has investigated the prognostic role of Bcl-2 in LUSC specifically. The present study aimed to comprehensively evaluate the prognostic value of Bcl-2 in LUSC. Microarray data for LUSC were downloaded from public databases, including the Gene Expression Omnibus and The Cancer Genome Atlas. Microarray data of 901 patients with LUSC from 16 data sets were retrieved. The meta-z algorithm was applied and the combined z score was identified as -2.43, suggesting Bcl-2 is a favorable prognostic biomarker. Furthermore, immunohistochemical staining of Bcl-2 expression was performed in a tissue microarray of 72 patients with LUSC and survival analysis demonstrated that patients with high expression Bcl-2 exhibited significantly more improved overall survival rates compared with those with low Bcl-2 expression. Multivariate Cox regression revealed that high expression of Bcl-2 is an independent favorable prognostic factor (hazard ratio, 0.295; confidence interval, 0.097-0.904; P<0.05). Therefore, the results of the present study demonstrated that Bcl-2 is a favorable prognostic biomarker in LUSC. [ABSTRACT FROM AUTHOR]

The role of microRNA (miRNA)-452-5p in lung squamous cell carcinoma (LUSC) remains unclear. Therefore, the present systematic study was performed to investigate the clinical significance and the rudimentary mechanism of the function of miR-452-5p in LUSC. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to confirm the expression level and clinical value of miR-452-5p in LUSC. Using online databases and bioinformatic software, gene ontology (GO), pathway and protein-protein interaction (PPI) analyses of miR-452-5p target genes were performed to examine the molecular mechanism of miR-452-5p. The association between the expression of miR-452-5p and that of its hub genes was verified using TCGA. Based on TCGA data on 387 clinical specimens, the expression of miR-452-5p in LUSC was significantly increased compared with adjacent lung tissues (7.1525±1.39063 vs. 6.0885±0.35298; P<0.001). The expression levels of miR-452-5p were significantly correlated with age (P=0.001) and tumor-node metastasis stage (P=0.028). Furthermore, the increased expression of miR-452-5p in LUSC compared with non-cancerous tissue [standard mean deviation (SMD), 0.372; 95% confidence interval (CI), 0.020-0.724; z=2.07; P=0.038] was validated by a meta-analysis of 720 clinical samples. The GO and pathway analyses revealed that miR-452-5p target genes were mainly enriched in the 'regulation of transcription', 'nucleoplasm', 'protein binding' and 'cell cycle' pathways. A total of 10 hub genes were identified by PPI analysis, and 5 hub genes (SMAD4, SMAD2, CDKN1B, YWHAE and YWHAB) were significantly enriched in the 'cell cycle' pathway. The expression of CDKN1B was negatively correlated with miR-452-5p (P=0.003). It was concluded that miR-452-5p may serve an essential role in the occurrence and progression of LUSC by targeting CDKN1B, which is involved in the cell cycle. [ABSTRACT FROM AUTHOR]

The study aim was to evaluate the association of the expression of serum microribonucleic acid-590 (miR-590) with the risk of lung squamous cell carcinoma (LUSC), clinicopathological staging and prognosis. A total of 237 patients with LUSC and 100 healthy volunteers (control group) were included in the study. Total RNA was extracted from the peripheral blood serum of the subjects, and the expression level of miR-590 was detected by reverse transcription realtime quantitative polymerase chain reaction. The baseline clinicopathological information of LUSC patients was evaluated, and the patients were followed up with the median follow-up of 47 months. Compared with that in the control group, the expression level of serum miR-590 in LUSC patients was significantly decreased [0.532 (0.367-0.821) vs. 1.63 (0.893-1.347), P<0.001]. The receiver operating characteristic (ROC) curve showed that the value of predicting LUSC risk using miR-590 was high, the area under curve (AUC) was 0.883, and 95% confidence interval (CI) was 0.829-0.934. In addition, the expression level of serum miR-590 was correlated with pathological staging (P=0.022), lymph node metastasis (P=0.012), distant metastasis (P<0.001) and tumor, node and metastasis (TNM) staging (P=0.044). The overall survival (OS) of patients in the serum miR-590 low expression group was significantly lower than that of the serum miR-590 high expression group (P=0.012), and the low expression of miR-590 was an independent risk factor for the prognosis of patients [hazard ratio (HR)=2.152, 95% CI=1.285-3.233, P=0.004]. The results suggested that the expression level of miR-590 can be used as a biomarker for the risk of disease, disease staging and prognosis of LUSC patients. [ABSTRACT FROM AUTHOR]

CDKN1A-interacting zinc finger protein 1 (CIZ1), a nuclear protein that participates in DNA replication, is involved in the pathogenesis of several types of cancer. However, the role of CIZ1 in lung squamous cell carcinoma (LSCC) is not fully understood. In the present study, the expression of CIZ1 in tissue microarrays and surgical samples of human LSCCs was examined. CIZ1 expression was found to be significantly increased in LSCC tissues compared with adjacent tissues or normal controls, whereas expression of a CIZ1-interacting protein, p21Cip1/Waf1, was decreased. CIZ1 staining intensity and CIZ1-positive vascular invasion were positively correlated with at least two categories of the Tumor-Node-Metastasis (TNM) staging system (T stage, N stage or TNM stage). It was also observed that CIZ1 was specifically expressed in the vascular cells of LSCC tissues. These results indicate that overexpression of CIZ1 may contribute to the growth and angiogenesis of LSCC, thus CIZ1 could represent a biomarker for diagnosis and a target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation is associated with non-small cell lung cancer (NSCLC), suggesting that gene promoter methylation may be a potential biomarker for the detection or risk prediction of NSCLC. The present study aimed to evaluate the potential usage of angiotensin II receptor type 1 (AGTR1) methylation in two major pathologic subtypes: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Quantitative methylation-specific polymerase chain reaction was used to investigate the effect of AGTR1 promoter methylation in the tumor and the paired adjacent non-tumor tissue samples from 42 patients with LUSC, and 69 with LUAD. The percentage of methylated reference was calculated and presented as the median (interquartile range 25th-75th percentile). The results of the current study revealed that there was significantly increased AGTR1 promoter methylation in the tumor tissues compared with the paired adjacent non-tumor tissue [97.4 (57.22-130.5) vs. 85 (48.25-123); P=0.024]. Furthermore, higher AGTR1 promoter methylation was observed in patients with LUSC compared with LUAD (odds ratio=2.483; 95% confidence interval=1.125-5.480; P=0.023). Significant differences were identified in AGTR1 methylation between non-tumor and the tumor tissues in LUSC [113.5 (68.33-148.73) vs. 93.04 (45.94-140); P=0.008]. In addition, the Cancer Genome Atlas data of 378 patients with LUSC and 477 with LUAD revealed an inverse correlation between gene expression and the methylation status of AGTR1 promoter.. These data suggest that AGTR1 hypermethylation is a promising biomarker to assist in LUSC detection and diagnosis. [ABSTRACT FROM AUTHOR]

Immunomodulatory therapy is a potential effective treatment for advanced cancer that may provide an alternative to chemotherapy, which patients can experience adverse side effects to. Myeloid‑derived suppressor cells (MDSCs) have been demonstrated to cause T‑cell tolerance in rodents and humans; however, little is known about the role of MDSCs in squamous cell carcinoma. In the present study, the role of MDSCs in lung squamous cell carcinoma was investigated. Peripheral blood from 78 patients with lung squamous cell carcinoma and 30 healthy controls was examined for the presence and function of human MDSCs, denoted as monocyte differentiation antigen CD14‑positive HLA class II histocompatibility antigen DR‑negative/low (CD14+HLA‑DR‑/low) cells by flow cytometry. The sorted T‑cell surface glyoprotein CD3 (CD3)+ cells and CD14+HLA‑DR‑/low cells were subsequently co‑cultured with a tumor cell line (NCI‑H226). T‑cell apoptosis was detected using annexin‑V‑fluorescein isothicyanate and 7‑aminoactinomycin D. Interferon‑γ (IFN‑γ) levels were detected using an ELISA. The frequency of MDSCs in the peripheral blood mononuclear cells (PBMCs) from patients with lung squamous cell carcinoma was significantly higher compared with that of the healthy controls (P<0.05), whereas the frequency of T‑cell surface glyoprotein CD4 (CD4)+ T cells and CD8+ T cells in PBMCs was significantly decreased (P<0.05). In an MDSC/CD8+ co‑culture system, the proportion of CD8+ T‑cell apoptosis significantly increased with the increase in ratio of MDSCs (P<0.05), while the proportion of tumor cell apoptosis significantly decreased (P<0.05). The concentration of IFN‑γ significantly decreased with the increase in MDSCs (P<0.05). Therefore, MDSCs participate in the immune escape of lung squamous cell carcinoma, and may provide a possible therapeutic strategy for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) remains the most frequent malignancy worldwide, and lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) represent two major subtypes. LINC00628 has been demonstrated to promote LUAD progression; however, its clinical role in NSCLC remains elusive. The aim of the present study was to analyze the expression of long intergenic non-protein coding RNA 628 (LINC00628) in NSCLC, including in the LUAD and LUSC subtypes. In addition, its roles in NSCLC development and prognosis were also examined. Data from The Cancer Genome Atlas (TCGA) database were first used to assess the expression and prognostic potential in both LUAD and LUSC, then LINC00628 expression in 128 NSCLC tissues was measured using reverse transcription-quantitative PCR. A receiver operating characteristic curve was used to assess the ability of LINC00628 to discriminate between patients with LUAD and LUSC. Kaplan-Meier curves were used to analyze the relationship between LINC00628 expression and the overall survival of patients. Cox regression analysis was used to explore the potential prognostic factors that might be independently associated with NSCLC overall survival. Both in silico and tissue analysis data indicated that the expression of LINC00628 was significantly upregulated in NSCLC tissue compared with matched normal controls (P<0.001). LINC00628 expression levels were also significantly higher in LUAD cases than in patients with LUSC (P<0.001). In addition, LINC00628 could discriminate LUAD from LUSC cases. The expression of LINC00628 was significantly associated with tumor size (P=0.013), histological type (P=0.009), lymph node metastasis (P=0.021) and TNM stage (P=0.008). Survival analysis based on data from both TCGA and patients included in the present study identified an association between LINC00628 and overall survival in LUAD, but this relationship was not observed in LUSC for TCGA data. Cox regression analysis demonstrated that high LINC00628 expression was associated with poor overall survival in patients with LUAD (P=0.001), but not in patients with LUSC (P=0.088). In conclusion, LINC00628 expression was upregulated in NSCLC and associated with patient prognosis. Patients with LUAD had higher LINC00628 expression levels than those with LUSC, and increased LINC00628 served as an independent prognostic factor in LUAD, but not LUSC. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) is one of the most common subtypes of lung cancer that accounts for ~50% of all lung cancer cases. Long noncoding RNA (lncRNA) PSMG3-antisense (AS) 1 has been suggested to play an important role in various types of cancer. Therefore, the aim of the present study was to investigate the role of PSMG3-AS1 using clinical specimens and data from 130 patients with LUSC. The expression levels of PSMG3-AS1 and miR-143-3p were detected in LUSC specimens, and the correlation between lncRNA PSMG3-AS1 expression and patient clinical characteristics was analyzed. Cell Counting Kit-8, Transwell migration and invasion assays were used to investigate the functional role of PSMG3-AS1 in LUSC. The mechanism of PSMG3-AS1 on LUSC cells was also investigated using a luciferase activity assay with wild-type or mutated PSMG3-AS1. PSMG3-AS1 was found to be upregulated in LUSC, and high expression was associated with positive lymph node metastasis and a higher TNM stage. The results of multivariate Cox regression analysis revealed that PSMG3-AS1 may serve as an independent prognostic indicator in LUSC. Furthermore, inhibiting PSMG3-AS1 expression reduced tumor cell proliferative, migratory and invasive abilities. Moreover, PSMG3-AS1 was found to be closely associated with miR-143-3p in LUSC, and thus may become a potential prognostic marker and therapeutic target for the treatment of LUSC in the future. [ABSTRACT FROM AUTHOR]

The determination of biomarkers in the blood specific for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is crucial for the selection of effective treatment strategies and the prediction of prognosis. The purpose of the present study was to analyze the differentially expressed genes (DEGs) in LUSC and LUAD from The Cancer Genome Atlas (TCGA) database. In order to identify the potential biomarkers for non-small cell lung cancer (NSCLC) for clinical diagnosis, bioinformatics was used to analyze the DEGs of two subtypes of NSCLC, LUAD and LUSC. Exosomes were isolated from the serum of patients with LUAD or LUSC and identified using transmission electron microscopy, nanoparticle tracking analysis and western blot analysis. A total of four differential exosomal mRNAs were selected for validation with serum samples from 70 patients with NSCLC via reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curves were established to evaluate the clinical diagnostic value of four DEGs for patients with LUAD and LUSC. The analysis based on TCGA data revealed the DEGs in LUSC and LUAD: A total of 1,619 genes were differentially expressed in patients with LUSC and LUAD. DEGs analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that inflammation-related signaling pathways, such as complement pathways, and multiple autoimmune diseases, such as systemic lupus erythematosus and asthma were mainly enriched in LUAD. The cell cycle, Hippo signaling pathway, Rap1 signaling pathway and Wnt signaling pathway were the main signaling pathways enriched in LUSC. The combination of tumor protein P63 (TP63), keratin 5 (KRT5), CEA cell adhesion molecule 6 (CEACAM6) and surfactant protein B (SFTPB) improved the specificity and sensitivity in the diagnosis of different lung cancer subtypes. Exosomal TP63, KRT5, CEACAM6 and SFTPB mRNAs can thus be used as biomarkers to differentiate between LUSC and LUAD, and may provide a novel strategy for their differential diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Although targeted therapy has achieved a great breakthrough in the treatment of lung adenocarcinoma, there are still no effective targeted drugs for lung squamous cell carcinoma (SqCC). In addition, as immunotherapy can only prolong the overall survival (OS) of lung SqCC by ≤5 months, chemotherapy and radiotherapy are still the main types of therapy for advanced SqCC. The expression level of epithelial growth factor receptor (EGFR) in patients with lung SqCC is higher compared with those with adenocarcinoma, but the former group is intrinsically resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Therefore, if the drug resistance in patients with lung SqCC could be reversed, the majority of patients may benefit from EGFR-TKIs. In the present study, the high-throughput RNA interference technology was used to screen the genes involved in the EGFR-TKI erlotinib resistance of lung SqCCs, and integrin-linked kinase (ILK) was identified to be the most effective. The role of ILK in erlotinib resistance was further studied in cell lines, and the expression of ILK was analyzed in patients with SqCC and adenocarcinoma. Finally, the mechanism of ILK in EGFR-TKIs resistance was analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and ingenuity pathway analysis (IPA). The results demonstrated that the ILK gene knockdown could overcome erlotinib resistance by inhibiting cell proliferation, inducing apoptosis and blocking the cell cycle at the G2/M phase. The expression of ILK in patients with SqCC was significantly higher compared with those with adenocarcinoma with sensitizing EGFR mutations. In addition, the cell cycle pathway 'G2/M DNA damage and checkpoint regulation' was identified to be significantly inhibited by ILK knockdown in IPA, KEGG and GO analysis. The results of the present study may improve the understanding of EGFR-TKI resistance in lung SqCCs, thus promoting the development of potential targeted therapies for lung SqCCs. [ABSTRACT FROM AUTHOR]

Previous studies have suggested increased activity of phosphatidylethanolamine binding protein 4 (PEBP4) may be associated with the prognosis of non-small cell lung cancer. However, to the best of our knowledge, no direct association between PEBP4 and lung squamous cell carcinoma (LSCC) has been reported. In the present study, a systematic review and meta-analysis was performed to examine the gene expression activity of PEBP4 in LSCC. A total of 10 out of 131 gene expression datasets from the Gene Expression Omnibus (GEO) were selected, including 574 samples (319 patients with LSCC and 255 healthy controls). Subsequently, multiple linear regression (MLR) was employed to study three potential influencing factors: Sample size, population region and study date. A literature-based pathway analysis was then conducted to examine the potential mechanisms through which PEBP4 may exert influence on LSCC. The results of a meta-analysis indicated that, in LSCC, PEBP4 exhibited significantly low expression levels (P<0.033), with mildly increased gene expression levels observed in three studies (log fold-change: 0.072-2.13). However, a significant between-study variance was observed from the heterogeneity analysis. MLR indicated that population region was a significant factor (P<0.0065), whereas sample size and study age were not (P>0.46). Eight functional pathways were subsequently identified, through which PEBP4 may influence the prognosis of LSCC and its response to treatment. The results of the present study suggested that the effects of PEBP4 on LSCC can be neglected in most cases of LSCC, where PEBP4 demonstrated decreased expression levels. However, in the case of PEBP4 overexpression, it may contribute to the progression of LSCC and lead to the development of drug resistance., (Copyright: © Yu et al.)

Lung squamous cell carcinoma (LUSC) progression is accompanied by changes in protein levels that may be reflected in body fluids, such as plasma, bronchoalveolar lavage fluid (BALF) and urine. Certain proteins present in these biofluids can facilitate lung cancer diagnosis. Kininogen 1 (KNG1), osteopontin (OPN) and α-1-antitrypsin (AAT) are associated with tumorigenesis. The present study aimed to explore the combined monitoring of plasma, urine and BALF to gain insight into LUSC by monitoring the levels of the above three protein using ELISA. LUSC (n=31) and healthy controls with benign lung diseases (n=20) were enrolled in the study. KNG1 levels in plasma, BALF and urine were significantly higher in patients with LUSC patients than in controls (P<0.0001, P<0.0001 and P=0.0010, respectively). OPN was upregulated in the plasma and BALF of patients with LUSC relative to controls (P=0.0107 and P=0.0004, respectively), whereas its levels in the urine of healthy controls were significantly higher (P=0.0088). Patients with LUSC had higher AAT levels in plasma, BALF and urine compared with those of the controls (P=0.0022, P=0.0014 and P=0.0005, respectively). Receiver operating characteristic analysis showed an area under the curve (AUC) of 0.81 for KNG1 in plasma, 0.91 in BALF and 0.81 in urine. The AUC for OPN was 0.71 in plasma, 0.83 in BALF and 0.75 in urine. The AUC for AAT was 0.74 in plasma, 0.74 in BALF and 0.86 in urine. Immunohistochemical staining in 20 paired LUSC and adjacent normal tissues showed that KNG1, OPN and AAT levels were higher in LUSC tissues. Therefore, our results showed that KNG1, OPN and AAT in biofluids might be useful for the diagnosis of LUSC. These markers in urine and BALF may be better than in plasma for detecting LUSC., (Copyright: © Wang et al.)

Aberrant DNA methylation is associated with non-small cell lung cancer (NSCLC), suggesting that gene promoter methylation may be a potential biomarker for the detection or risk prediction of NSCLC. The present study aimed to evaluate the potential usage of angiotensin II receptor type 1 ( AGTR1 ) methylation in two major pathologic subtypes: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Quantitative methylation-specific polymerase chain reaction was used to investigate the effect of AGTR1 promoter methylation in the tumor and the paired adjacent non-tumor tissue samples from 42 patients with LUSC, and 69 with LUAD. The percentage of methylated reference was calculated and presented as the median (interquartile range 25th-75th percentile). The results of the current study revealed that there was significantly increased AGTR1 promoter methylation in the tumor tissues compared with the paired adjacent non-tumor tissue [97.4 (57.22-130.5) vs. 85 (48.25-123); P=0.024]. Furthermore, higher AGTR1 promoter methylation was observed in patients with LUSC compared with LUAD (odds ratio=2.483; 95% confidence interval=1.125-5.480; P=0.023). Significant differences were identified in AGTR1 methylation between non-tumor and the tumor tissues in LUSC [113.5 (68.33-148.73) vs. 93.04 (45.94-140); P=0.008]. In addition, the Cancer Genome Atlas data of 378 patients with LUSC and 477 with LUAD revealed an inverse correlation between gene expression and the methylation status of AGTR1 promoter.. These data suggest that AGTR1 hypermethylation is a promising biomarker to assist in LUSC detection and diagnosis.

Immunomodulatory therapy is a potential effective treatment for advanced cancer that may provide an alternative to chemotherapy, which patients can experience adverse side effects to. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to cause T-cell tolerance in rodents and humans; however, little is known about the role of MDSCs in squamous cell carcinoma. In the present study, the role of MDSCs in lung squamous cell carcinoma was investigated. Peripheral blood from 78 patients with lung squamous cell carcinoma and 30 healthy controls was examined for the presence and function of human MDSCs, denoted as monocyte differentiation antigen CD14-positive HLA class II histocompatibility antigen DR-negative/low (CD14 + HLA-DR -/low ) cells by flow cytometry. The sorted T-cell surface glyoprotein CD3 (CD3) + cells and CD14 + HLA-DR -/low cells were subsequently co-cultured with a tumor cell line (NCI-H226). T-cell apoptosis was detected using annexin-V-fluorescein isothicyanate and 7-aminoactinomycin D. Interferon-γ (IFN-γ) levels were detected using an ELISA. The frequency of MDSCs in the peripheral blood mononuclear cells (PBMCs) from patients with lung squamous cell carcinoma was significantly higher compared with that of the healthy controls (P<0.05), whereas the frequency of T-cell surface glyoprotein CD4 (CD4) + T cells and CD8 + T cells in PBMCs was significantly decreased (P<0.05). In an MDSC/CD8 + co-culture system, the proportion of CD8 + T-cell apoptosis significantly increased with the increase in ratio of MDSCs (P<0.05), while the proportion of tumor cell apoptosis significantly decreased (P<0.05). The concentration of IFN-γ significantly decreased with the increase in MDSCs (P<0.05). Therefore, MDSCs participate in the immune escape of lung squamous cell carcinoma, and may provide a possible therapeutic strategy for the treatment of this disease.