Adjacent Non-tumor Lung Tissues Research Articles

CASTOR1 phosphorylation as a predictor of survival in male patients with KRAS-mutated lung adenocarcinoma.

e20015 Background: Lung cancer, a leading global cause of cancer-related mortality, necessitates enhanced prognostic markers for improved treatment outcomes. This study focuses on the predictive value of phosphorylated cytosolic arginine sensor for mTORC1 subunit 1 at S14 (pCASTOR1) in lung adenocarcinoma (LUAD) patients, specifically in males with KRAS mutations. Methods: This retrospective study, approved by University of Pittsburgh IRB, utilized formaline-fixed paraffin embedded primary tissues from two independent cohorts of patients who underwent thoracic surgical procedures at the University of Pittsburgh Medical Center (UPMC) from 2002 to 2011. Comprehensive clinical, demographical and pathological information was obtained from UPMC Cancer Registry, with cases lacking incomplete information excluded from analysis. Study endpoints included overall survival (OS) and relapse-free survival (RFS). An antibody targeting pCASTOR1 was employed to analyze LUAD tumor and adjacent non-tumor lung tissues from both cohorts. A pathologist, blinded to patient information and survival outcomes, conducted scoring in 5% increments. Scores were categorized as low or high pCASTOR1 based on second or third quartile. Correlations between pCASTOR1 scores and OS/RFS were examined, stratifying by clinical, pathological, demographic, or genotype data. Univariate OS and RFS analyses were conducted using the Kaplan-Meier method and log-rank test, while multivariate survival significance was assessed via Cox regression analysis. Additionally, unpaired T-tests were utilized to compare pCASTOR1 levels between non-tumor and tumor cells. A significance threshold of p < 0.05 was applied for all analyses. Results: Tumor cells exhibited significantly elevated pCASTOR1 scores compared to non-tumor cells in both cohorts (P < 0.05). High pCASTOR1 scores predicted poor OS (HR = 3.3, P = 0.0008) and RFS (HR = 3.0, P = 0.0035) in male patients with KRAS mutations in Cohort 1. pCASTOR1 remained an independent predictor for OS (HR = 4.1, P = 0.0047) and RFS (HR = 3.5, P = 0.0342) after controlling for other factors. Cohort 2, comprised solely of smokers with incomplete genotype information, validated these findings, with high pCASTOR1 scores correlating with worse OS (HR = 4.8, P = 0.0363). Notably, in early-stage LUAD, elevated pCASTOR1 scores were associated with significantly worse OS (HR = 3.3, P = 0.0176) and RFS (HR = 3.1, P = 0.0277) in male patients with KRAS mutations in Cohort 1, and worse OS (HR = 5.0, P = 0.0069) and RFS (HR = 5.0, P = 0.0069) in Cohort 2, akin to late-stage patients. Conclusions: Elevated pCASTOR1 score serves as a robust biomarker predicting poor OS and RFS in male LUAD patients with KRAS mutations, offering potential clinical utility in optimizing treatment strategies for this subgroup.

Establishment of a prognostic model towards lung squamous cell carcinoma based on m7G-related genes in TCGA.

Lung squamous cell carcinoma (LUSC) is a non-small cell lung cancer with a poor prognosis owing to late diagnosis. New molecular markers are urgently needed to improve the diagnosis and prognosis of LUSC. 7-Methylguanosine (m7G) modifications-a transfer RNA (tRNA) modification-are common in eubacteria, eukaryotes, and a few archaea. These modifications promote the turnover and stability of some mRNAs to prevent mRNA decay, improve translation efficiency, and reduce ribosomal pausing but are associated with poor survival in human cancer cells. However, the expression of m7G-related genes in LUSC and their association with prognosis remain unclear. In this study, we identified nine differentially expressed genes related to prognosis by comparing the expression profiles of tumor tissues (502 LUSC reports) with normal tissues (49 adjacent non-tumor lung tissue reports). The genes included six upregulated (KLK7, LCE3E, AREG, KLK6, ZBED2, and MAPK4) and three downregulated (ADH1C, NTS, and ERLIN2) genes. Based on these nine genes, patients with LUSC were classified into low- and high-risk groups to analyze the trends in prognosis. We found that the nine m7G-related genes play important roles in immune regulation, hormone regulation, and drug sensitivity through pathways, including antigen processing and presentation, adherent plaques, ECM receptor interactions, the drug metabolism of cytochrome p450, and the metabolism of cytochrome p450 to xenobiotics; the functions of these genes are likely accomplished in part by m6A modifications. The effect of m7G-related genes on the diagnosis and prognosis of LUSC was further indicated by population analysis.

Clinical significance of STING expression and methylation in lung adenocarcinoma based on bioinformatics analysis

The role of stimulator of interferon genes [STING, also known as transmembrane protein 173 (TMEM173)] in various human cancers has begun to emerge. However, the clinical value of STING in lung adenocarcinoma (LUAD) remains elusive. This study aims to elucidate the clinical significance of STING expression and methylation in LUAD. Here, through analyzing data from public resources, we found that both the mRNA and protein expression of STING were reduced in lung cancer. Moreover, lower expression of STING was associated with a worse prognosis in LUAD, but not lung squamous cell carcinoma (LUSC). Of note, higher methylation of STING was found in LUAD and had the potential to distinguish LUAD tissues from adjacent non-tumor lung tissues and correlated with unfavorable outcomes. Furthermore, the methylation of STING could serve as an independent prognostic indicator for both the overall survival (OS) and disease-free survival (DFS) of LUAD patients. Additionally, the constructed nomogram exhibited a favorable predictive accuracy in predicting the probability of 1- and 2-year OS. Our findings suggest that the mRNA expression, and especially the DNA methylation of STING, have the potential to be prognostic indicators for LUAD patients.

Prognostic Significance of HMGA1 Expression in Lung Cancer Based on Bioinformatics Analysis.

High-mobility group protein 1 (HMGA1) participates in the processes of DNA transcription, replication, recombination, and repair. The HMGA1 gene is expressed abundantly during embryogenesis and is reactivated during carcinogenesis. HMGA1 gene expression has been associated with a high degree of malignancy, metastatic tendency, and poor survival in breast, colon, ovary, and pancreatic cancers. However, its prognostic significance in lung cancer remains unclear. Using publicly available data, HMGA1 was shown to be overexpressed in both small and non-small lung tumors, with higher expression compared to both the adjacent non-malignant lung tissues and non-tumor lung tissues of healthy individuals. Elevated HMGA1 expression could result from lowered HMGA1 methylation and was connected with some clinicopathological features like sex, age, and stage of the disease. The high HMGA1 expression level was connected with shorter overall and first progression survival time among lung adenocarcinoma patients, but not lung squamous cell carcinoma patients. HMGA1 could interact with proteins involved in cellular senescence and cell cycle control (TP53, RB1, RPS6KB1, and CDK1), transcription regulation (EP400 and HMGA2), chromatin assembly and remodeling (LMNB1), and cholesterol and isoprene biosynthesis (HMGCR and INSIG1). Taken together, HMGA1 overexpression could be an essential element of lung carcinogenesis and a prognostic feature in lung cancer.

Proteome profiling of formalin‑fixed, paraffin‑embedded lung adenocarcinoma tissues using a tandem mass tag‑based quantitative proteomics approach

Over the past few decades, increasing efforts have been made to improve the understanding of, and treatment options for, lung adenocarcinoma (LUAD). However, considering the heterogeneity of LUAD, precise proteomics-based characterization at the molecular level is an urgent clinical requirement for effective treatment. Formalin-fixed, paraffin-embedded (FFPE) tissue is a good option as the working tool for proteomics studies. The present study aimed to obtain a global protein profile using LUAD FFPE tissue samples. Using a quantitative proteomics approach, the study revealed that 360 proteins were significantly more highly expressed in LUAD than in adjacent nontumor lung tissues. Also, 19 differentially expressed membrane proteins were found to be primarily responsible for immune processes. Epidermal growth factor (EGF)-like domain and laminin EGF domain showed markedly different expression levels between cancer tissues and tumor-adjacent normal tissues. Furthermore, Gene Ontology functional enrichment analysis showed that significantly upregulated proteins were associated with the endoplasmic reticulum lumen, protein disulfide isomerase activity, vitamin binding, cell cycle G1/S phase transition, to name but a few. Also, numerous kinases and post-translational modification enzymes were significantly upregulated across all eight LUAD samples compared with paracarcinoma tissues. Proteomics analysis revealed that AAA domain containing 3A (ATAD3a), a member of the ATPase family, was highly expressed in LUAD tissues, which was supported by immunohistochemical analysis. Furthermore, the study confirmed that ATAD3a enhanced the cisplatin sensitivity of LUAD cells. Collectively, the findings of the present study provide new potential candidate targets in patients with LUAD, and may aid auxiliary LUAD diagnosis and surveillance in a noninvasive manner.

SLC39A5 promotes lung adenocarcinoma cell proliferation by activating PI3K/AKT signaling

Lung cancer is the most common cancer and the primary cause of cancer-related deaths worldwide. Solute carrier family 39 member 5 (SLC39A5) regulates cellular zinc homeostasis and plays a vital role in several human cancers. However, the clinical significance and biological function of SLC39A5 in lung adenocarcinoma (LUAD) remain unclear. Hence, we sought to elucidate the role of SLC39A5 in LUAD pathophysiology in this study. The expression and clinical significance of SLC39A5 were evaluated using The Cancer Genome Atlas, the Gene Expression Omnibus, and tissue microarray data. We used the Cell Counting Kit-8, flow cytometry, western blotting, and quantitative reverse transcriptase-polymerase chain reaction analyses to determine the function of SLC39A5 in vitro. We also used a mouse xenograft model to evaluate the function of SLC39A5 in vivo. Our results indicate that SLC39A5 was upregulated in LUAD tissues compared with that in adjacent non-tumor lung tissues. SLC39A5 overexpression correlated with poor survival in patients with LUAD. SLC39A5 promoted LUAD cell proliferation by accelerating the G1-to-S phase transition and inhibiting apoptosis. SLC39A5 knockdown inhibited the tumorigenesis of LUAD cells in a nude mouse model of xenograft tumors. SLC39A5 promoted LUAD cell proliferation by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling. SLC39A5 played an oncogenic role in LUAD by activating the PI3K/AKT signaling. Hence, SLC39A5 may serve as a novel prognostic biomarker and potential therapeutic target for LUAD.

Overexpression of CENPF is associated with progression and poor prognosis of lung adenocarcinoma.

Background and aim: The molecular signatures of lung adenocarcinoma (LUAD) are not well understood. Centromere protein F (CENPF) has been shown to promote oncogenesis in many cancers; however, its role in LUAD has not been illustrated. We explored the role of CENPF in LUAD.Methods: CENPF expression level was investigated in public online database firstly, the prognosis of CENPF in LUAD were also assessed by Kaplan-Meier analysis. Then quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed using 13 matched pairs of clinical LUAD tissue samples. Subsequently, the impact of CENPF expression on cell proliferation, cell cycle, apoptosis, colony formation was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometric analysis and colony formation assay, respectively. Finally, experimental xenograft lung cancer model of nude mice armpit of right forelimb to determine the effect of CENPF on LUAD tumorigenesis.Results: CENPF mRNA expression was significantly elevated in LUAD tissues compared with adjacent non-tumor lung tissues in Gene Expression Profiling Interactive Analysis (GEPIA) (P < 0.001). Up-regulated CENPF was remarkably positively associated with pathological stage, relapse free survival (RFS) as well as overall survival (OS) of LUAD patients. Besides, CENPF knockdown greatly suppressed A549 cell proliferation, induced S phase arrest, promoted apoptosis and decreased colony numbers of LUAD cells. Furthermore, knockdown of CENPF significantly inhibited the tumor growth of the LUAD cells in an experimental xenograft lung cancer model of nude mice armpit of right forelimb.Conclusion: Taken together, these results demonstrated that CENPF may serve as a potential biomarker of prognostic relevance and a potential therapeutic target for LUAD.

Correlation of microRNA-335 expression level with clinical significance and prognosis in non-small cell lung cancer.

Although treatments have improved significantly in recent years, the prognosis of patients with non-small cell lung cancer (NSCLC) remains poor. miR-335 has been demonstrated to play the antitumor role in several cancer types. Its expression was reduced in NSCLC tissues relative to noncancerous adjacent tissues. Furthermore, downregulation of miR-335 in A459 lung cancer cells promoted cell proliferation. In the present study, we aimed to investigate the clinical significance and prognostic value of miR-335 in NSCLC.The lung cancer tissues and adjacent nontumor lung tissues were obtained from 131 patients who underwent the primary surgical resection at Lianyungang First People's Hospital. Student t test was used to distinguish differences between groups. χ2 test was involved for analysis of clinicopathological data. The overall survival was analyzed by the Kaplan-Meier method and the log rank test. Multiple Cox proportional hazards regression analysis was carried out to identify the independent factors that had a significant impact on patient survival.miR-335 was significantly lower in NSCLC samples compared to non-cancerous samples (P < .001). The expression level of miR-335 was significantly correlated with tumor histology (P = .028), lymph node metastasis (P = .002), differentiation degree (P < .001), and pathological TNM stage (P < .001). The log-rank test indicated that patients with decreased miR-335 expression experienced poor overall survival in NSCLC (P = .029).The results of the present study indicated that miR-335 was down-expressed in NSCLC, and is associated with tumor progression and poor prognosis, suggesting that the expression of miR-335 might be an independent prognostic factor of overall survival in patients with NSCLC.

Whole genomic copy number variation score: an indicator of potential diagnostic and prognostic value for lung adenocarcinoma

Objective: To verify the value of whole genomic copy number variation (WGCNV) detection and scoring system in the diagnosis and prognosis of lung adenocarcinoma. Methods: Seventy-six lung adenocarcinoma specimens including ninety-one tumor samples and twenty adjacent non-tumor lung tissue samples were collected using Laser capture microdissection (LCM). Whole genomic amplification (WGA) was used to enrich DNA and construct a sequencing library for next generation sequencing (NGS). Changes of larger than 5Mb CNV in this study were analyzed and scored. The nuclear grading and score of tumor cells in the surgery and pleural effusion cytology of lung adenocarcinoma specimens were evaluated separately. For each case, we evaluated (1) nuclear size, (2) mitotic counts, (3) nuclear atypia, (4) atypical mitoses. The data of disease-free survive (DFS) and overall survive (OS) were collected for assessing the prognostic value of WGCNV score. Meanwhile, receiver operating characteristic (ROC) and area under curve (AUC) were used to define a cut-off value and evaluate the diagnostic significance in lung adenocarcinoma. Results: The WGCNV scores of twenty adjacent non-tumor lung tissue samples were treated as normal control and all of WGCNV scores of tumor samples range from 0 to 9.95, the median score was 2.7. The WGCNV scores were divided into three groups: low score group <1.74, medium score grade 1.74~4.23, high score grade >4.23. The WGCNV score was positively associated with the nuclear grade scoring (r=0.780 90, P<0.001). The result for evaluation of prognostic value of the WGCNV scores showed that comparing with low WGCNV score group, Hazard Ratio (HR) of medium score group was 4.11 (95%CI=0.72~23.57) and high score group was 2.07 (95%CI=0.30~14.12). These results suggested that the risks of the medium and high WGCNV score group elevated. According to the analysis results of ROC curve, when the cut off value was 0.01, the sensitivity and specificity for lung adenocarcinoma diagnosis were 97.8% and 95.0% respectively, the positive predictive value (PPV) and negative predictive value (NPV) were 99.0% and 90.1%, respectively, the AUC was 0.981. In the differentiation of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) group and invasive adenocarcinoma group, when the cut off value was 1.8, the sensitivity and specificity between the two groups were 78.1% and 94.4%, and the PPV and NPV were 98.0% and 52.0%, respectively, the AUC was 0.896. Conclusion: This study verifies that WGCNV scoring system has a potential diagnostic and prognostic value in lung adenocarcinoma.

AMPK α1 Downregulates ROS Levels Through Regulating Trx Leading to Dysfunction of Apoptosis in Non-Small Cell Lung Cancer.

PurposeAMP-activated protein kinase α1 (AMPK α1) associates closely with cancers. However, the relationship between AMPK α1 and non-small cell lung cancer (NSCLC) is not fully understood. In this study, we aim to explore the role and mechanism of AMPK α1 in NSCLC initiation and progression.Materials and MethodsA total of 165 clinical NSCLC specimens were included in the formalin-fixed and paraffin-embedded (FFPE) lung cancer tissue arrays. The expression levels of AMPK α1 and thioredoxin (Trx) in NSCLC cancer tissues and adjacent non-tumor lung tissues were measured through using immunohistochemistry. MTT assay was used to detect cell proliferation. Intracellular ROS levels were measured by using H2DCFDA reagent. Lentiviruses including LV-PRKAA1-RNAi, LV-PRKAA1 and a negative LV-control were used to infect A549 cells to modulate AMPK α1 expression in vitro. Immunoblotting was used to determine the modulation relationship between AMPK α1 and Trx. Log rank test and Kaplan–Meier survival analysis were performed to evaluate the significances of AMPK α1 and Trx expression levels on NSCLC patients’ prognoses.ResultsAMPK α1 was highly expressed in NSCLC cancer tissues and correlated with poor prognosis in patients with NSCLC. In A549 cells, overexpression of AMPK α1 promoted proliferation, suppressed ROS levels and inhibited apoptosis. Moreover, inhibition of AMPK α1 expression achieved the opposite effects. Trx was significantly overexpressed in NSCLC cancer tissues; furthermore, Trx expressed much more in cytoplasm when compared with cell nucleus. Trx expression levels were positively correlated with AMPK α1 expression levels in NSCLC tissues. AMPK α1 could regulate Trx in A549 cells. No significant correlations were observed between Trx expression variances and prognoses in NSCLC patients. Combination of AMPK α1 and Trx had no advantage in predicting prognoses of NSCLC patients.ConclusionThese results suggest that AMPK α1 serves a carcinogenic role at least in part through the regulation of Trx expression, and thus represents a potential treatment target in patients with NSCLC.

Clinical Significance of SERPINA1 Gene and Its Encoded Alpha1-antitrypsin Protein in NSCLC.

High expression of SERPINA1 gene encoding acute phase protein, alpha1-antitrypsin (AAT), is associated with various tumors. We sought to examine the significance of SERPINA1 and AAT protein in non-small-cell lung cancer (NSCLC) patients and NSCLC cell lines. Tumor and adjacent non-tumor lung tissues and serum samples from 351 NSCLC patients were analyzed for SERPINA1 expression and AAT protein levels. We also studied the impact of SERPINA1 expression and AAT protein on H1975 and H661 cell behavior, in vitro. Lower SERPINA1 expression in tumor but higher in adjacent non-tumor lung tissues (n = 351, p = 0.016) as well as higher serum levels of AAT protein (n = 170, p = 0.033) were associated with worse survival rates. Specifically, in NSCLC stage III patients, higher blood AAT levels (>2.66 mg/mL) correlated with a poor survival (p = 0.002). Intriguingly, levels of serum AAT do not correlate with levels of C-reactive protein, neutrophils-to-leukocyte ratio, and do not correlate with SERPINA1 expression or AAT staining in the tumor tissue. Additional experiments in vitro revealed that external AAT and/or overexpressed SERPINA1 gene significantly improve cancer cell migration, colony formation and resistance to apoptosis. SERPINA1 gene and AAT protein play an active role in the pathogenesis of lung cancer and not just reflect inflammatory reaction related to cancer development.

MicroRNA-510 Plays Oncogenic Roles in Non-Small Cell Lung Cancer by Directly Targeting SRC Kinase Signaling Inhibitor 1.

An increasing number of studies have demonstrated that microRNAs (miRNAs) may play key roles in various cancer carcinogenesis and progression, including non-small cell lung cancer (NSCLC). However, the expressions, roles, and mechanisms of miR-510 in NSCLC have, up to now, been largely undefined. In vivo assay showed that miR-510 was upregulated in NSCLC tissues compared with that in adjacent nontumor lung tissues. miR-510 expression was significantly correlated with TNM stage and lymph node metastasis. In vitro assay indicated that expressions of miR-510 were also increased in NSCLC cell lines. Downregulation of miR-510 suppressed NSCLC cell proliferation and invasion in vitro. We identified SRC kinase signaling inhibitor 1 (SRCIN1) as a direct target gene of miR-510 in NSCLC. Expression of SRCIN1 was downregulated in lung cancer cells and negatively correlated with miR-510 expression in tumor tissues. Downregulation of SRCIN1, leading to inhibition of miR-510 expression, reversed cell proliferation and invasion in NSCLC cells. These results showed that miR-510 acted as an oncogenic miRNA in NSCLC, partly by targeting SRCIN1, suggesting that miR-510 can be a potential approach for the treatment of patients with malignant lung cancer.

Abstract 1602: Genomic profiling of lung cancer associated with idiopathic pulmonary fibrosis

Abstract Idiopathic pulmonary fibrosis (IPF) is reportedly associated with an increased risk of lung cancer. However, optimal diagnosis and treatment for lung cancer associated with IPF remains unclear. In this study, we aimed to clarify the mechanism of carcinogenesis and progression in lung cancer with IPF. We used tumor tissues and adjacent non-tumor lung tissues from 29 lung cancer patients who had undergone complete surgical resection at Nippon Medical School Hospital between 2013 and 2017. Whole-Exon Sequencing was performed on 29 paired samples, consisted of 19 lung cancers with IPF (IPF group) and 10 lung cancers with normal lung (non-IPF group). The candidate gene alterations discriminating between the IPF and non-IPF group, were identified using the random-forest method, RelifF method along with the data from Catalogue Of Somatic Mutations In Cancer (COSMIC). Twenty-five gene alterations were specifically found in IPF tissues and/or tumor tissues with IPF. Whenever 5 of 25 genes including MUC2 and TTF1, were altered in both IPF tissues and tumor tissues, 20 of 25 genes including CADM1, were altered in only tumor tissues. We are undergoing the validation study using other tissues in independent cohorts. Among the candidate genes, Cell adhesion molecule genes (CADM1) gene alterations were frequently found in 15 out of 19 in only tumor tissues with IPF. The CADM1 protein expression was decreased in tumors than in non-tumor fibrotic tissues by western blotting. The CADM1 induced the epithelial-mesenchymal transition (EMT) on the multifunctional cell process involved in the pathogenesis of fibrosis in vitro study. Whenever the down-regulation of CADM1 was frequently detected in various human cancers through its allelic loss as well as hypermethylation within promoter region in addition to inactivate gene mutation, the up-regulation of CADM1 was frequently detected in paired IPF tissues. The CADM1 may be a target candidate in lung cancer associated with IPF. Citation Format: Rintaro Noro, Akihiko Miyanaga, Aya Fukuizumi, Shinobu Kunugi, Teppei Sugano, Miwako Omori, Yuji Minegish, Jitsuo Usuda, Masahiro Seike, Kaoru Kubota, Mamiko Hirao, Kuniko Matsuda, Akihiko Gemma. Genomic profiling of lung cancer associated with idiopathic pulmonary fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1602.

Analysis of the long non-coding RNA LINC01614 in non-small cell lung cancer

The aim of this study was toexplore the long non-coding RNA (lncRNA) expression pattern of non-small cell lung cancer (NSCLC) on a genome-wide scale and investigate their potential biological function in NSCLC.LncRNAs were investigated in 6 pairs of NSCLC and matched adjacent non-tumor lung tissues (NTL) by microarray. A validation cohort was obtained from The Cancer Genome Atlas (TCGA) database and the effect of LINC01614 on diagnosis and prognosis in NSCLC was analyzed. Gene set enrichment analysis (GSEA) was used to predict the potential molecular mechanism of LINC01614, one identified lncRNA.A total of 1392 differentially expressed lncRNAs were identified. LINC01614 was the most aberrantly expressed lncRNA in NSCLC compared with NTL. We confirmed the significantly upregulated LINC01614 in NSCLC patients from TCGA database. Furthermore, in TCGA database, LINC01614 was significantly upregulated in both adenocarcinoma and squamous cell carcinoma. And high expression of LINC01614 indicated poor overall survival of NSCLC patients. A sensitivity of 93% was calculated conditional on a high specificity of 95% for the discrimination of NSCLC tissues from normal tissues. Furthermore, the expression levels of LINC01614 were associated with the stage of tumor, but had no relationship with age and sex. Additionally, GSEA found that LINC01614 might be involved in TGF-β-, P53-, IGF-IR-mediated, Wnt and RTK/Ras/MAPK signaling pathways.lncRNAs may play key roles in the development of NSCLC. LINC01614 is the most aberrantly expressed lncRNA in NSCLC tissues in our experiment and is also significantly differentially expressed in NSCLC patients from TCGA database. LINC01614 could be a prognostic indicator and has the potential to be a diagnostic biomarker of NSCLC.

AMP‑activated protein kinase α1 serves a carcinogenic role via regulation of vascular endothelial growth factor expression in patients with non‑small cell lung cancer

AMP-activated protein kinase α1 (AMPK α1) is involved in the tumorigenesis of various cancer types. However, the role of AMPK α1 in non-small cell lung cancer (NSCLC) remains unclear. In the present study, 99 NSCLC tumor tissues and paired normal tissues were obtained. The expression levels of AMPK α1 were significantly upregulated in NSCLC tumor tissues compared with those in adjacent non-tumor lung tissues. The patients were further divided into two groups according to their expression levels of AMPK α1 in tumor tissues. The results outlined that overexpression of AMPK α1 was associated with poor prognosis. In addition, vascular endothelial growth factor (VEGF) expression levels were associated with malignant progression in patients with NSCLC. Patients with NSCLC that overexpressed AMPK α1 and VEGF had the worst outcomes. Moreover, AMPK α1 may positively regulate VEGF expression. These results suggest that AMPK α1 serves a carcinogenic role at least in part through the regulation of VEGF expression, and thus represents a potential treatment target in patients with NSCLC.

Correction: Identification of novel gene expression signature in lung adenocarcinoma by using next-generation sequencing data and bioinformatics analysis.

[This corrects the article DOI: 10.18632/oncotarget.21022.].

Overexpression of LncRNA-UCA1 Correlates with Lung Adenocarcinoma Progression and Poor Prognosis.

Long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been predicted to play a critical role in various biological processes including tumorigenesis. However, the clinical significance of UCA1 in lung adenocarcinoma (LUAD) is still not understood in detail. The aim of this study was to assess the clinical significance of the UCA1 expression levels in LUAD based on publicly available data and to evaluate its potential signaling pathways. The RNA-sequencing (RNA-seq) dataset and clinical information of all LUAD patients were downloaded from The Cancer Genome Atlas (TCGA). Kaplan-Meier plot and log-rank test were performed for survival analysis; Cox proportional hazards regression model were used to assess the relative factors. Furthermore, Starbase, Cbioportal, and Multi Experiment Matrix starbases were used to identify UCA1-related genes in LUAD. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of UCA1-related genes were performed using DAVID. The expression level of UCA1 in LUAD tissues (n = 468) was significantly increased compared with the adjacent non-tumor lung tissues (n = 52) (p < 0.0001). In addition, UCA1 level was significantly correlated with TNM stage and lymph node metastasis. Survival analysis showed that UCA1 over-expression was significantly associated with poor overall survival (OS) (p = 0.0098) and poor recurrence-free survival (RFS) (p = 0.0298) in LUAD patients. Multivariate analysis confirmed that high expression of lncRNA-UCA1 was an independent prognostic factor of poor OS (HR = 1.353, 95% CI: 1.005 - 1.822, p = 0.046). Finally, KEGG analysis for UCA1-related genes indicated that UCA1 might be enriched with the microRNAs in cancer, pathways in cancer, endocytosis, focal adhesion, and proteoglycans in cancer. This study showed that UCA1 may be involved in lung carcinogenesis, which could act as a biomarker of prognosis and therapeutic target in LUAD patients.

Transcriptomic and functional network features of lung squamous cell carcinoma through integrative analysis of GEO and TCGA data

Lung squamous cell carcinoma (LUSC) is associated with poor clinical prognosis and lacks available targeted therapy. Novel molecules are urgently required for the diagnosis and prognosis of LUSC. Here, we conducted our data mining analysis for LUSC by integrating the differentially expressed genes acquired from Gene Expression Omnibus (GEO) database by comparing tumor tissues versus normal tissues (GSE8569, GSE21933, GSE33479, GSE33532, GSE40275, GSE62113, GSE74706) into The Cancer Genome Atlas (TCGA) database which includes 502 tumors and 49 adjacent non-tumor lung tissues. We identified intersections of 129 genes (91 up-regulated and 38 down-regulated) between GEO data and TCGA data. Based on these genes, we conducted our downstream analysis including functional enrichment analysis, protein-protein interaction, competing endogenous RNA (ceRNA) network and survival analysis. This study may provide more insight into the transcriptomic and functional features of LUSC through integrative analysis of GEO and TCGA data and suggests therapeutic targets and biomarkers for LUSC.

A novel SWIM domain protein ZSWIM5 inhibits the malignant progression of non-small-cell lung cancer.

PurposeZinc finger SWIM-type containing 5 (ZSWIM5) is a newly discovered protein, which contains a novel zinc-chelating domain SWIM (CxCxnCxH), and is predicted to interact with DNA or proteins. Currently, the knowledge of functions of ZSWIM5 remains limited. In this study, we aimed to elucidate the biological functions of ZSWIM5 and their mechanisms.Patients and methodsWe detected the expression of ZSWIM5 in samples from 139 cases of non-small-cell lung cancer (NSCLC) patients and six cell lines using immunohistochemistry and Western blot. Moreover, we explored the biological functions of ZSWIM5 in lung cancer cells by siRNA interference and cDNA transfection of ZSWIM5.ResultsThe results showed that compared with adjacent non-tumor lung tissues, ZSWIM5 expression was significantly decreased in NSCLC tissues (P=0.0199) and that the ZSWIM5-positive rate in non-tumor tissues (76.67%) was notably higher than that in NSCLC tissues (40.29%). ZSWIM5 expression in human normal bronchial epithelial cells was also much higher than that in lung cancer lines (P<0.001). ZSWIM5-negative expression was significantly related to TNM stage (P<0.001), lymph node metastasis (P=0.002), and poor prognosis (P<0.001) of NSCLC patients. MTT and colony formation assays showed that ZSWIM5 could inhibit the proliferation and colony formation abilities of lung cancer cells. Meanwhile, the results of transwell and wound healing assays showed that ZSWIM5 could suppress the invasion and migration of lung cancer cells. Further investigation revealed that ZSWIM5 could downregulate cyclin D1, cyclin E, cyclin A2, MMP2, and MMP9 expression, which affected the proliferation, invasion, and migration abilities of lung cancer cells.ConclusionZSWIM5 could inhibit the malignant progression of NSCLC by affecting the expression of cyclins and MMPs.

Identification of novel gene expression signature in lung adenocarcinoma by using next-generation sequencing data and bioinformatics analysis.

Lung adenocarcinoma is one of the leading causes of cancer-related death worldwide. We showed transcriptomic profiles in three pairs of tumors and adjacent non-tumor lung tissues using next-generation sequencing (NGS) to screen protein-coding RNAs and microRNAs. Combined with meta-analysis from the Oncomine and Gene Expression Omnibus (GEO) databases, we identified a representative genetic expression signature in lung adenocarcinoma. There were 9 upregulated genes, and 8 downregulated genes in lung adenocarcinoma. The analysis of the effects from each gene expression on survival outcome indicated that 6 genes (AGR2, SPDEF, CDKN2A, CLDN3, SFN, and PHLDA2) play oncogenic roles, and 7 genes (PDK4, FMO2, CPED1, GNG11, IL33, BTNL9, and FABP4) act as tumor suppressors in lung adenocarcinoma. In addition, we also identified putative genetic interactions, in which there were 5 upregulated microRNAs with specific targets - hsa-miR-183-5p-BTNL9, hsa-miR-33b-5p-CPED1, hsa-miR-429-CPED1, hsa-miR-182-5p-FMO2, and hsa-miR-130b-5p-IL33. These 5 microRNAs have been shown to be associated with tumorigenesis in lung cancer. Our findings suggest that these genetic interactions play important roles in the progression of lung adenocarcinoma. We propose that this molecular change of genetic expression may represent a novel signature in lung adenocarcinoma, which may be developed for diagnostic and therapeutic strategies in the future.