Lung Squamous Cell Carcinoma Cases Research Articles

MiRNA-Seq Tissue Diagnostic Signature: A Novel Model for NSCLC Subtyping.

Non-small cell lung cancer (NSCLC) encompasses distinct histopathological subtypes, namely adenocarcinoma (AC) and squamous cell lung carcinoma (SCC), which require precise differentiation for effective treatment strategies. In this study, we present a novel molecular diagnostic model that integrates tissue-specific expression profiles of microRNAs (miRNAs) obtained through next-generation sequencing (NGS) to discriminate between AC and SCC subtypes of NSCLC. This approach offers a more comprehensive and precise molecular characterization compared to conventional methods such as histopathology or immunohistochemistry. Firstly, we identified 31 miRNAs with significant differential expression between AC and SCC cases. Subsequently, we constructed a 17-miRNA signature through rigorous multistep analyses, including LASSO/elastic net regression. The signature includes both upregulated miRNAs (hsa-miR-326, hsa-miR-450a-5p, hsa-miR-1287-5p, hsa-miR-556-5p, hsa-miR-542-3p, hsa-miR-30b-5p, hsa-miR-4728-3p, hsa-miR-450a-1-3p, hsa-miR-375, hsa-miR-147b, hsa-miR-7705, and hsa-miR-653-3p) and downregulated miRNAs (hsa-miR-944, hsa-miR-205-5p, hsa-miR-205-3p, hsa-miR-149-5p, and hsa-miR-6510-3p). To assess the discriminative capability of the 17-miRNA signature, we performed receiver operating characteristic (ROC) curve analysis, which demonstrated an impressive area under the curve (AUC) value of 0.994. Our findings highlight the exceptional diagnostic performance of the miRNA signature as a stratifying biomarker for distinguishing between AC and SCC subtypes in lung cancer. The developed molecular diagnostic model holds promise for providing a more accurate and comprehensive molecular characterization of NSCLC, thereby guiding personalized treatment decisions and improving clinical management and prognosis for patients.

Kallikrein-related peptidase 13 expression and clinicopathological features in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LSCC) is associated with poor prognosis. Molecular targeting drugs have been demonstrated to be effective for lung adenocarcinoma; however, they are often not effective for LSCC. Kallikrein-related peptidase 13 (KLK13) expression enhances the malignancy of lung adenocarcinoma; however, its expression and crucial role in LSCC remain largely unknown. The present study examined the relationship between the KLK13 expression and clinicopathological features of LSCC. A total of 94 patients diagnosed with LSCC who underwent lobectomy, segmentectomy or wedge resection were selected. KLK13 expression was evaluated through immunostaining of formalin-fixed paraffin-embedded sections of surgical specimens. Of the 94 LSCC samples, 70 exhibited no KLK13 expression, while the remaining 24 exhibited ectopic expression. KLK13 expression in tumors was focal and restricted to the cytoplasm of keratinized cells. LSCC cases were classified into KLK13-negative and KLK13-positive groups, and KLK13 expression was positively associated with E-cadherin expression (P=0.0143). Associations between KLK13 expression and keratinization (P=0.0052) or absence of lymphatic vessel invasion (P=0.0603) were observed; however, these trends did not reach statistical significance. The present findings indicated that KLK13 expression in keratinized LSCC may have a protective role in lymphatic vessel invasion of LSCC, which suggests its significance for therapeutic applications against LSCC.

Effect of sample size on prognostic genes analysis in non-small cell lung cancer.

The identification of prognostic genes can help in the clinical management of non-small cell lung cancer (NSCLC). However, there is little overlap in the prognostic genes identified in different NSCLC studies. One reason for this may be the inadequate sample size. Here, the effect of sample size on prognostic genes analysis was investigated based on 515 stage II/III NSCLC cases from two cohorts detected by whole-exome sequencing. Prognostic genes analysis was repeatedly performed 100 times for each sample size level using random resampling methods. In stage II lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cases from the TCGA Pan-Lung Cancer cohort, the number of statistically significant prognostic genes first increased with sample size in a power law, then fluctuated steadily, and finally decreased slightly. The power law growth curves were also observed in stage III LUAD and LUSC cases from the TCGA Pan-Lung Cancer cohort and stage III Chinese LUAD cases from the OncoSG cohort. The correlation R2 of the fitted power law growth curves were all greater than 0.99. In addition, at the sample size level where the number of prognostic genes peaked, the mean proportion of true prognostic genes in patients with stage II LUAD and LUSC was 28.32% and 23.12%, which could partly explain the little overlap in prognostic genes between reports. In conclusion, the number of prognostic genes takes a power law growth with the sample size in NSCLC, independent of histopathological subtype, race, and stage. These results also show how sample size affects the reliability of prognostic genes and will aid trial design for genomic mutation-based prognostic studies in NSCLC.

Tastin promotes non-small-cell lung cancer progression through the ErbB4, PI3K/AKT, and ERK1/2 pathways.

Tastin might be involved in tumorigenesis, but its role in non-small-cell lung cancer (NSCLC) has not been adequately explored. This work aimed to examine tastin's role in NSCLC and to explore the underlying mechanism. The Gene Expression Omnibus (GEO), Gene Expression Database of Normal and Tumor tissues (GENT), and Cancer Genome Atlas (TCGA) databases were used. Four GEO datasets (GSE81089, GSE40419, GSE74706, and GSE19188) containing gene expression data for NSCLC and normal tissue samples were analyzed for tastin mRNA expression. Tastin expression levels in different tissues were compared using the GENT website. TCGA biolinks were used to download gene expression quantification (n = 594) and overall survival data (n = 535). In total, 30 lung adenocarcinoma and 25 lung squamous cell carcinoma cases were enrolled. In addition, four-week-old male BALB/c nude mice (n = 9/group) were used to establish xenograft mouse models. Furthermore, cultured HEK293T, A549, and NCI-H226 cells assessed. Immunoblot, hematoxylin and eosin (H&E) staining, immunohistochemistry, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), fluorescence microscopy, flow cytometry, lentiviral transduction, and MTT, colony formation, wound healing, and Transwell assays were carried out. Tastin expression levels were markedly increased in NSCLC tumor tissue specimens and correlated with a poorer prognosis. Silencing of tastin inhibited the proliferative and migratory abilities of NSCLC cells. Bioinformatic analysis suggested that tastin interacts with ErbB4. The PI3K/AKT and ERK1/2 downstream pathways were suppressed in tastin-deficient cells. In conclusion, tastin might be involved in NSCLC growth and invasion and is a potential therapeutic target in NSCLC.

Digital Quantification of Tumor Cellularity as a Novel Prognostic Feature of Non–Small Cell Lung Carcinoma

Non-small cell lung carcinoma is currently staged based on the size and involvement of other structures. Tumor size may be a surrogate measure of the total number of tumor cells. A recently revised reporting system for adenocarcinoma incorporates high-risk histologic patterns, which may have increased cellular density. Modern digital image analysis tools can be utilized to automate the quantification of cells. In this study, we tested the hypothesis that tumor cellularity can be used as a novel prognostic tool for lung cancer. Digital slides from The Cancer Genome Atlas lung adenocarcinoma (ADC) data set (n= 213) and lung squamous cell carcinoma (SCC) data set (n= 90) were obtained and analyzed using QuPath. The number of tumor cells was normalized with the surface area of the tumor to provide a measure of tumor cell density. Tumor cellularity was calculated by multiplying the size of the tumor with the cell density. Major histologic patterns and grade were compared with the tumor density of the lung ADC and lung SCC cases. The overall and progression-free survival were compared between groups of high and low tumor cellularity. High-grade histologic patterns in the ADC and SCC cases were associated with greater tumor densities compared with low-grade patterns. Cases with lower tumor cellularity had improved overall and progression-free survival compared with cases with higher cellularity. These results support tumor cellularity as a novel prognostic tool for non-small cell lung carcinoma that considers tumor stage and grade elements.

What’s the difference between lung adenocarcinoma and lung squamous cell carcinoma? Evidence from a retrospective analysis in a cohort of Chinese patients

BackgroundLung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two most common subtypes of lung cancer. Previously, they were categorized into one histological subtype known as non-small cell lung cancer (NSCLC) and often treated similarly. However, increasing evidence suggested that LUAD and LUSC should be classified and treated as different cancers. But yet, detailed differences in clinical features between LUAD and LUSC have not been well described.MethodsA cohort of 142 Chinese patients with 111 LUAD and 31 LUSC cases were consecutively enrolled from April 2019 to October 2020 in Hunan Provincial People’s Hospital. The clinical features of the patients were retrospectively analyzed and compared in the terms of general information, clinicopathologic characteristics, imaging findings and laboratory data.ResultsIn comparison with LUAD, LUSC patients had a significantly higher proportion of males, smokers, drinkers, higher-stage cases. The mean tumor size in LUSC patients was significantly larger than that in LUAD patients. Compared with LUAD patients, more of patients with LUSC had cough, fever and abundant sputum symptoms. Besides that, more bacterial infections and fungal infections were found in LUSC patients than that in LUAD patients. Imaging data shows that ground-glass opacity and patchy shadows in radiological films were more frequent in LUAD patients than that in LUSC patients. In addition to initial laboratory data, LUSC patients had higher levels of leukocytes, platelets, and creatinine that of LUAD patients.ConclusionsTogether, these results suggested that there exist distinct differences between LUAD and LUSC subtypes; LUSC may be a more malignant type in comparison with LUAD. Our findings may have potential implications in clinical settings. However, further multicenter studies are needed to validate these findings in a larger sample size.

CD70 in Thymic Squamous Cell Carcinoma: Potential Diagnostic Markers and Immunotherapeutic Targets.

CD70 – a ligand protein of CD27 on lymphocytes – is expressed in a large spectrum of malignancies. It is an attractive target for antibody-based therapy and several clinical trials are currently being conducted. However, there is no evidence regarding the expression of CD70 and its relationship with expression of programmed death ligand-1 (PD-L1) and CD27+ tumor-infiltrating lymphocytes (TIL) in formalin-fixed paraffin-embedded (FFPE) tissues of thymic tumors. FFPE tissues of thymic squamous cell carcinoma (TSCC) (operative specimens, n = 31; biopsy specimens, n = 11), thymoma (n = 60), thymic carcinoid (n = 3), and lung squamous cell carcinoma (LSCC) (n = 30) were analyzed immunohistochemically. Immunoreactivity for CD70 was semi-quantitatively scored according to the proportion of positive tumor cells. Moreover, the densities of CD27-positive intratumoral TIL (iTIL) and stromal TIL of TSCC were assessed and survival was compared. Most TSCC cases (87%; 27/31) were CD70-positive. In contrast, all thymoma and thymic carcinoid cases were CD70-negative. In LSCC cases, CD70-positivity was significantly lower than TSCC cases (20%; 6/30). Biopsy and resected specimens obtained from the same patients demonstrated a consistent staining pattern (6/6 patients). The proportion of CD70-positive TSCC was comparable with those of CD5 (87%) and CD117 (90%). Correlation between CD70 and PD-L1 expression score was observed. There was no significant difference in survival between the CD70-high and CD70-low expression groups. Meanwhile, patients with CD27-positive iTIL-high tumors exhibited better survival than those with iTIL-low tumors. This tendency was weaker in the CD70-high subset. CD70 immunohistochemistry is useful in diagnosing TSCC. CD70 may prevent anti-tumor immunity via CD27. Immunotherapy targeting the CD70–CD27 axis may be a promising option for the treatment of TSCC.

Prognostic Value and Oncogenic Effects of Ubiquitin-Specific Protease 43 in Lung Squamous Cell Carcinoma.

Dysregulated expression of ubiquitin-specific protease 43 (USP43) has been recently discovered in malignancies. This study aimed to investigate the expression pattern of USP43 protein in lung squamous cell carcinoma (LUSC) and to explore its correlation with patients' clinicopathological characteristics as well as clinical outcomes. Expression of USP43 protein was determined by immunohistochemistry staining in a retrospective cohort containing 157 LUSC cases who underwent curative surgery in our hospital. Accordingly, USP43 protein was positively correlated with tumor size, depth of invasion, and lymph node metastasis. Patients with increased USP43 expression or positive lymph nodes exhibited a poorer overall survival. In addition, cellular assays elucidated that USP43 can promote LUSC growth and invasion. Taken together, our study demonstrated that USP43 may act as a proto-oncogene, which could be a promising biomarker and therapeutic target in the survival prediction and treatment of LUSC.

LINC00628 is differentially expressed between lung adenocarcinoma and squamous cell carcinoma and is associated with the prognosis of NSCLC.

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.

Aberrant expression of HIF3A in plasma of patients with non-small cell lung cancer and its clinical significance.

BackgroundHypoxia‐inducible factors (HIFs) have been evaluated in various cancers and diseases. However, the specific role of hypoxia‐inducible factor 3 alpha (HIF3A) in non‐small cell lung cancer (NSCLC) remains controversial.Materials and MethodsWe investigated HIF3A mRNA expression in the plasma and tumor tissues of patients with NSCLC and explored its clinical significance. Plasma samples from 103 cases of lung adenocarcinoma (LUAD) and 96 cases of lung squamous cell carcinoma (LUSC), and tumor‐adjacent normal tissues from 58 LUAD and 62 LUSC cases were retrospectively evaluated at the No.8 People's Hospital of Qing Dao. HIF3A expression was explored using RT‐qPCR. The clinical significance of HIF3A was evaluated in the plasma and tumor tissues using the receiver operating curve (ROC) and the area under the curve (AUC).ResultsHypoxia‐inducible factor 3 alpha expression was notably downregulated in the plasma or tumor tissues of patients with LUAD and LUSC, compared with the healthy control group or adjacent normal tissues. Furthermore, HIF3A expression had a significant positive correlation in the plasma and tumor tissues of LUAD and LUSC patients. Meanwhile, the ROC‐AUCs achieved a significantly higher range, from 0.84 to 0.93, with the plasma or tumor tissues of NSCLC patients. Thus, HIF3A expression was not only correlated with plasma and tumor tissues, but also showed potential significance in NSCLC.ConclusionHypoxia‐inducible factor 3 alpha is aberrantly detectable in NSCLC patients in the plasma and tumor tissues. HIF3A may be involved in hypoxic responses during the development and occurrence of NSCLC.

Intrapulmonic Cavity or Necrosis on Baseline CT Scan Serves as an Efficacy Predictor of Anti-PD-(L)1 Inhibitor in Advanced Lung Squamous Cell Carcinoma.

BackgroundPredictive markers for guidance and monitoring of immunotherapy in lung squamous cell carcinoma (LSCC) are an interesting topic but have yet to be fully explored. A primary characteristic of LSCC is tumor necrosis that results in extensive immune suppression in patients. We sought to assess whether tumor necrosis or cavity on baseline CT could effectively predict the efficacy of immune checkpoint inhibitors (ICIs) in advanced LSCC.MethodsAdvanced LSCC cases undergoing pre-treatment chest CT imaging and receiving ICIs were retrospectively collected. All CT images were reviewed by an independent chest radiologist blinded to any previous diagnosis to confirm morphological alterations in necrosis or cavity. We performed Logistic regression and developed Cox proportional hazards models to assess the predictive performance of baseline necrosis or cavity characteristics in advanced LSCC. Survival estimates were observed using Kaplan–Meier curves.ResultsNinety-three patients were eligible for analysis, predominantly consisting of patients with ECOG performance status of 0 or 1 (97.8%), male patients (95.7%), and heavy smokers (92.5%). Intrapulmonic necrosis or cavity on CT scan was present in 52.7% of all patients. Generally, the objective response rate (ORR) in patients with necrosis or cavity to ICI treatment was significantly worse versus those without (30.6% vs 54.5%, p = 0.020), with the subgroup ORRs as follows: ICI monotherapy (necrosis vs non-necrosis: 10.0% vs 36.8%, p =0.047) and ICI combination therapy (44.8% vs 68.0%, p =0.088). Multivariable analysis identified intrapulmonic necrosis or cavity at baseline as a major risk factor for advanced LSCC (HR 4.042, 95% CI1.149–10.908, p = 0.006). Multivariate Cox analysis showed that baseline necrosis or cavity and ICI monotherapy were unfavorable factors for progression-free survival (HR 1.729; 95% CI1.203–2.484, p =0.003).ConclusionLSCC patients with intrapulmonic cavity or necrosis on baseline CT scan may respond poorly to anti-PD-(L)1-treatment, monotherapy and combination therapy alike.

TMEM229A suppresses non‑small cell lung cancer progression via inactivating the ERK pathway.

Transmembrane protein 229A (TMEM229A) is a member of the TMEM family that plays an important role in tooth differentiation and development. However, the expression level and biological role of TMEM229A in cancer remains unknown. The present study aimed to investigate the expression level of TMEM229A in non-small cell lung cancer (NSCLC), as well as its effect and mechanism on NSCLC progression. Clinical specimens from patients with NSCLC were enrolled from the First People's Hospital of Huzhou (Huzhou, China). TMEM229A expression was detected using reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemical analysis. The relationship between TMEM229A expression and the survival rate of patients with NSCLC was analyzed using Kaplan-Meier Plotter datasets. The effects of TMEM229A on cell proliferation, migration and invasion were detected using Cell Counting Kit-8, colony formation, soft agar, real-time cellular analysis and Transwell assays. The expression levels of epithelial-mesenchymal transition (EMT)-related proteins, as well as ERK and AKT phosphorylation were determined via RT-qPCR and western blot analysis. The results demonstrated that TMEM229A expression was significantly downregulated in human NSCLC tissues and in several cell lines compared with adjacent normal lung tissues and BEAS-2B cells, respectively. Survival analysis of lung adenocarcinoma and squamous cell lung carcinoma cases identified that low TMEM229A expression was associated with a poor prognosis. The in vitro assays indicated that overexpressing TMEM229A significantly inhibited cell proliferation, migration and invasion, while TMEM229A knockdown had the opposite effect. Mechanistically, TMEM229A overexpression effectively increased E-cadherin expression and reduced N-cadherin, snail family transcriptional repressor 1 and MMP2 expression, indicating that EMT was suppressed. In addition, overexpression of TMEM229A reduced the expression levels of phosphorylated (p)-ERK and p-AKT, and this effect was partially suppressed by the incorporation of specific ERK inhibitor PD98059. Collectively, the results of the present study demonstrated that the effects of TMEM229A on inhibiting cell proliferation, migration and invasion were partially mediated by inactivating the ERK signaling pathway, thereby providing a potential therapeutic target for the treatment of NSCLC.

Low Expression of ADCY4 Predicts Worse Survival of Lung Squamous Cell Carcinoma Based on Integrated Analysis and Immunohistochemical Verification.

PurposeThe molecular mechanism underlying the carcinogenesis and development of lung squamous cell carcinoma (LUSC) has not been sufficiently elucidated. This analysis was performed to find pivotal genes and explore their prognostic roles in LUSC.MethodsA microarray dataset from GEO (GSE19188) and a TCGA-LUSC dataset were used to identify differentially co-expressed genes through Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis. We conducted functional enrichment analyses of differentially co-expressed genes and established a protein-protein interaction (PPI) network. Then, we identified the top 10 hub genes using the Maximal Clique Centrality (MCC) algorithm. We performed overall survival (OS) analysis of these hub genes among LUSC cases. GSEA analyses of survival-related hub genes were conducted. Ultimately, the GEO and The Human Protein Atlas (THPA) databases and immunohistochemistry (IHC) results from the real world were used to verify our findings.ResultsA list of 576 differentially co-expressed genes were selected. Functional enrichment analysis indicated that regulation of vasculature development, cell−cell junctions, actin binding and PPAR signaling pathways were mainly enriched. The top 10 hub genes were selected according to the ranking of MCC scores, and 5 genes were closely correlated with OS of LUSC. Additionally, GSEA analysis showed that spliceosome and cell adhesion molecules were associated with the expression of GNG11 and ADCY4, respectively. The GSE30219 and THPA databases and IHC results from the real world indicated that although GNG11 was not detected, ADCY4 was obviously downregulated in LUSC tissues at the mRNA and protein levels.ConclusionsThis analysis showed that survival-related hub genes are highly correlated to the tumorigenesis and development of LUSC. Additionally, ADCY4 is a candidate therapeutic and prognostic biomarker of LUSC.

Thyroid hormone receptor α1 acts as a new squamous cell lung cancer diagnostic marker and poor prognosis predictor: Can it be a novel therapeutic target?

e20508 Background: Lung cancer is considered the first cause of cancer-related death worldwide. Unfortunately, all therapeutic regimens used in lung cancer treatment showed relatively equivalent efficacy. The search and subsequent testing of new therapeutic targets that can be used alternative to, after the failure of or in association with the currently used therapeutics to improve the prognosis is an urgent demand and consequently a very interesting era of oncological lung research. Up to date, it is known that Thyroid hormones and Thyroid hormone receptors (THRs) controls many tumors progression, nevertheless, its role in non-Small Cell Lung cancer (NSCLC) is not yet defineltly understood. This study investigated the expression of Thyroid hormone receptor alpha 1 (THRα1) in NSCLC cases. Methods: Immunohistochemistry using THRα1 antibody was performed on tissue sections collected from 80 patients diagnosed with NSCLC. We also analyzed the expression of THRα gene in Microarrays of squamous cell lung carcinoma (SCC) and adenocarcinoma (AC) patients by using GEO datasets on https://www.ncbi.nlm.nih.gov. Results: We showed, for the first time, the expression of THRa1 in NSCLC. Intermediate and high THRa1 expression was detected in (25% and 66.7%) of SCC cases respectively. High THRa1 expression was associated with shorter OS and poor prognosis. On the other hand, 86.7% of AC cases revealed low THRa1expression. By analyzing GEO data sets, a significant increase in THRa gene value was found in SCC compared to AC cases. Inflammatory cells in SCC cases showed high THRα1 expression. Conclusions: Our study is shedding a new light on the relevance of THRα1 in lung cancer not only as a possible prognostic marker but also as an innovative diagnostic additive tool for lung squamous cell carcinoma which could be tested as a therapeutic target as well.

Expression, Prognosis and Gene Regulation Network of NFAT Transcription Factors in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. The nuclear factor of activated T cells (NFAT) family is implicated in tumorigenesis and progression in various types of cancer. However, little is known about their expression patterns, distinct prognostic values, and potential regulatory networks in NSCLC. In this study, we comprehensively analyzed the distinct expression and prognostic value of NFATs in NSCLC through various large databases, including the Oncomine, UCSC Xena Browser, UALCAN databases, Kaplan–Meier Plotter, cBioPortal, and Enrichr. In lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), NFAT1/2/4/5 mRNA expression levels were significantly decreased and NFAT3 mRNA expression level was significantly increased. The cBioPortal database analysis showed that the mRNA dysregulation was one of the single most important factors for NFAT alteration in LUAD and LUSC and that both LUAD and LUSC cases with the alterations in the mRNA expression of NFATs had significantly better overall survival (OS). High expression levels of NFAT1/2/4/5 were significantly associated with better OS in LUAD, whereas high NFAT3 expression led to a worse OS. Overexpression of NFAT1/2 predicted better OS in LUSC, whereas high NFAT5 expression led to a worse OS. The networks for NFATs and the 50 most frequently altered neighbor genes in LUAD and LUSC were also constructed. NFATs and genes significantly associated with NFAT mRNA expression in LUAD and LUSC were significantly enriched in the cGMP-dependent protein kinase and Wnt signaling pathways. These results showed that the NFAT family members displayed varying degrees of abnormal expressions, suggesting that NFATs may be therapeutic targets for patients with NSCLC. Aberrant expression of NFATs was found to be associated with OS in the patients with NSCLC; among NFATs, NFAT3/4 may be new biomarkers for the prognosis of LUAD. However, further studies are required to validate our findings.

Postoperative radiotherapy for patients with completely resected pathological stage IIIA-N2 non-small cell lung cancer: a preferential benefit for squamous cell carcinoma.

BackgroundThe beneficial effect of postoperative radiotherapy (PORT) on completely resected pathological IIIA-N2 (pIIIA-N2) non-small cell lung cancer (NSCLC) has been a subject of interest with controversy. The aim of the study was to distinguish the clinical efficacy of PORT on lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC) among pIIIA-N2 NSCLC.Patients and methodsBetween October 2010 and September 2016, 288 consecutive patients with completely resected pIIIA-N2 NSCLC at Beijing Chest Hospital were retrospectively analyzed, which consisted of 194 cases of LADC and 85 cases of LSCC. There were 42 (21.6%) patients treated with PORT in LADC cases and 19 (22.3%) patients treated with PORT in LSCC cases. The 5-year overall survival (OS), loco-regional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The prognostic factors were determined using Cox’s regression model.ResultsAmong 194 cases of LADC, the 1-, 3-, and 5-year OS in the PORT group were 95.2%, 61.9% and 40.0%, respectively, while in the non-PORT group were 90.1%, 63.3% and 45.0% (p = 0.948). The use of postoperative chemotherapy (POCT) and smoking index ≥ 400 were both prognostic factors of 5-year rates of OS, LRFS and DMFS. On the other hand, among 85 cases of LSCC, the 1-, 3-, and 5-year OS in the PORT group were 94.7%, 63.2% and 63.2%, respectively, whereas in the non-PORT group were 86.4%, 48.5% and 37.1% (p = 0.026). In this group, only the use of PORT was a favorable prognostic factor for 5-year OS, LRFS and DMFS.ConclusionsDue to clinicopathological differences among completely resected pIIIA-N2 NSCLC, PORT may not be suitable to all patients. Our study distinguishes pIIIA-N2 LSCC from LADC by their positive responses to PORT.

Detection of human papillomavirus distinguishes second primary tumors from lung metastases in patients with squamous cell carcinoma of the cervix.

BackgroundIn patients with squamous cell carcinoma of the cervix (SCCC), a squamous cell carcinoma (SqCC) in the lung represents either a second primary tumor or metastasis. This distinction between second primary tumors and lung metastases in patients with SCCC significantly influences patient prognosis and therapy. Here, we aimed to differentiate second primary tumors from lung metastases in patients with SCCC by exploring the HPV status in SqCCs involving the lung within a large cohort.MethodsP16 expression was assessed using immunohistochemistry on tissue microarrays including a total of 415 primary lung SqCCs and 21 lung SqCCs with prior SCCC. Following this, we performed HPV DNA typing and the sensitive RNAscope in situ method to screen all the cases for HPV E6/E7 expression, which is a more reliable indicator of transcriptively active HPV in tumor cells.ResultsThe p16 positive expression rate was 13.7% (57/415) in primary lung SqCCs, but HPV DNA was not detected in any of the 57 primary lung SqCC cases that positively expressed p16. In contrast, HPV DNA was detected in all cases (21/21) with prior SCCC. Consistently, all 21 lung SqCCs with prior SCCC (21/21) showed extensive HPV16 E6/E7 expression. In striking contrast, none of the primary lung SqCCs (0/415) had a detectable RNAscope signal.ConclusionsHPV does not seem to play a role in the development of primary lung SqCCs. HPV detection may be helpful in distinguishing second primary tumors from lung metastases in patients with SCCC.

Expression of p42.3 in non-small cell lung cancer.

BackgroundLung cancer is the most malignant tumor with the highest morbidity and mortality. This study aimed to investigate the role of the expression and the significance of the p42.3 gene in non-small cell lung cancer (NSCLC).MethodsLung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were analyzed based on the biological information data of The Cancer Genome Atlas (TCGA). Furthermore, 142 postoperative tumor tissue and normal tissue samples (70 cases of LUAD and 72 cases of LUSC) from NSCLC patients admitted to our hospital from 2005 to 2009 were retrospectively collected. Paraffin-embedded tissues were used to make the tissue microarrays (TMA), and the expression of the p42.3 protein was detected by immunohistochemical staining.ResultsThe expression of p42.3 in both LUAD and LUSC was significantly upregulated (P<0.01) compared with the normal lung tissues. The p42.3 expression was significantly higher than that of LUAD (P<0.01) in the LUSC group. LUSC had a lower level of p42.3 DNA methylation and a higher level of p42.3 DNA amplification than LUAD. The expression rate of p42.3 protein decreased in patients 70 years or older (P=0.029). High expression of the p42.3 protein was an independent factor for worse pathological differentiation (P=0.043).ConclusionsBoth genetic and epigenetic alterations contributed to dysregulated p42.3 in NSCLC. Despite the temporary absence of TCGA-LUSC (TCGA data on LUSC) survival information, we observed that the up-regulated expression of p42.3 in LUSC was significantly higher than that in LUAD by analyzing the public database and reviewing the real-world data. Furthermore, a high expression of p42.3 protein was significantly correlated with poor differentiation of tumor tissues. Therefore, the prognostic value of p42.3 in LUSC deserves further study.

PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma.

Previous studies showed that PPAR-gamma (PPARG) ligands might serve as potential therapeutic agents for nonsmall cell lung cancer (NSCLC). However, a few studies reported the specific relationship between PPARG and lung squamous cell carcinoma (LSCC). Here, we made an effort to explore the relationship between PPARG and LSCC. First, we used mega-analysis and partial mega-analysis to analyze the effects of PPARG on LSCC by using 12 independent LSCC expression datasets (285 healthy controls and 375 LSCC cases). Then, literature-based molecular pathways between PPARG and LSCC were established. After that, a gene set enrichment analysis (GSEA) was conducted to study the functionalities of PPARG and PPARG-driven triggers within the molecular pathways. Finally, another mega-analysis was constructed to test the expression changes of PPARG and its driven targets. The partial mega-analysis showed a significant downregulated expression of PPARG in LSCC (LFC = −1.08, p value = 0.00073). Twelve diagnostic markers and four prognostic markers were identified within multiple PPARG-LSCC regulatory pathways. Our results suggested that the activation of PPARG expression may inhibit the development and progression of LSCC through the regulation of LSCC upstream regulators and downstream marker genes, which were involved in tumor cell proliferation and protein polyubiquitination/ubiquitination.

PEBP4 gene expression in lung squamous cell carcinoma: A meta-analysis-based study of the molecular pathways involved.

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.