Deregulated microRNAs Are Associated with Patient Survival and Predicted to Target Genes That Modulate Lung Cancer Signaling Pathways

(1) Background: Although the advances in diagnostic and treatment strategies, lung cancer remains the leading cause of cancer-related deaths, worldwide, with survival rates as low as 16% in developed countries. Low survival rates are mainly due to late diagnosis and the lack of effective treatment. Therefore, the identification of novel, clinically useful biomarkers is still needed for patients with advanced disease stage and poor survival. Micro(mi)RNAs are non-coding RNAs and potent regulators of gene expression with a possible role as diagnostic, prognostic and predictive biomarkers in cancer. (2) Methods: We applied global miRNA expression profiling analysis using TaqMan® arrays in paired tumor and normal lung tissues (n = 38) from treatment-naïve patients with lung adenocarcinoma (AD; n = 23) and lung squamous cell carcinoma (SCC; n = 15). miRNA target genes were validated using The Cancer Genome Atlas (TCGA) lung AD (n = 561) and lung SCC (n = 523) RNA-Seq datasets. (3) Results: We identified 33 significantly deregulated miRNAs (fold change, FC ≥ 2.0 and p < 0.05) in tumors relative to normal lung tissues, regardless of tumor histology. Enrichment analysis confirmed that genes targeted by the 33 miRNAs are aberrantly expressed in lung AD and SCC, and modulate known pathways in lung cancer. Additionally, high expression of miR-25-3p was significantly associated (p < 0.05) with poor patient survival, when considering both tumor histologies. (4) Conclusions: miR-25-3p may be a potential prognostic biomarker in non-small cell lung cancer. Genes targeted by miRNAs regulate EGFR and TGFβ signaling, among other known pathways relevant to lung tumorigenesis.

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Identification of Novel microRNA Prognostic Markers Using Cascaded Wx, a Neural Network-Based Framework, in Lung Adenocarcinoma Patients

Cancers ◽

10.3390/cancers12071890 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1890 ◽

Cited By ~ 1

Author(s):

Jeong Seon Kim ◽

Sang Hoon Chun ◽

Sungsoo Park ◽

Sieun Lee ◽

Sae Eun Kim ◽

...

Keyword(s):

Neural Network ◽

Lung Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Patient Survival ◽

Survival Rates ◽

The Cancer Genome Atlas ◽

Lung Cancer Cells ◽

Mesenchymal Transition ◽

Next Generation Sequencing Technology

The evolution of next-generation sequencing technology has resulted in a generation of large amounts of cancer genomic data. Therefore, increasingly complex techniques are required to appropriately analyze this data in order to determine its clinical relevance. In this study, we applied a neural network-based technique to analyze data from The Cancer Genome Atlas and extract useful microRNA (miRNA) features for predicting the prognosis of patients with lung adenocarcinomas (LUAD). Using the Cascaded Wx platform, we identified and ranked miRNAs that affected LUAD patient survival and selected the two top-ranked miRNAs (miR-374a and miR-374b) for measurement of their expression levels in patient tumor tissues and in lung cancer cells exhibiting an altered epithelial-to-mesenchymal transition (EMT) status. Analysis of miRNA expression from tumor samples revealed that high miR-374a/b expression was associated with poor patient survival rates. In lung cancer cells, the EMT signal induced miR-374a/b expression, which, in turn, promoted EMT and invasiveness. These findings demonstrated that this approach enabled effective identification and validation of prognostic miRNA markers in LUAD, suggesting its potential efficacy for clinical use.

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UBE2D1 RNA Expression Was an Independent Unfavorable Prognostic Indicator in Lung Adenocarcinoma, but Not in Lung Squamous Cell Carcinoma

Disease Markers ◽

10.1155/2018/4108919 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Liyan Hou ◽

Yingbo Li ◽

Ying Wang ◽

Dongqiang Xu ◽

Hailing Cui ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Lung Adenocarcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Survival Data ◽

Lung Squamous Cell Carcinoma ◽

Prognostic Indicator ◽

The Cancer Genome Atlas ◽

Rna Expression

In this study, we investigated the potential prognostic value of ubiquitin-conjugating enzyme E2D1 (UBE2D1) RNA expression in different histological subtypes of non-small-cell lung cancer (NSCLC). A retrospective study was performed by using molecular, clinicopathological, and survival data in the Cancer Genome Atlas (TCGA)—Lung Cancer. Results showed that both lung adenocarcinoma (LUAD) (N=514) and lung squamous cell carcinoma (LUSC) (N=502) tissues had significantly elevated UBE2D1 RNA expression compared to the normal tissues (p<0.001 and p=0.036, respectively). UBE2D1 RNA expression was significantly higher in LUAD than in LUSC tissues. Increased UBE2D1 RNA expression was independently associated with shorter OS (HR: 1.359, 95% CI: 1.031–1.791, p=0.029) and RFS (HR: 1.842, 95% CI: 1.353–2.508, p<0.001) in LUAD patients, but not in LUSC patients. DNA amplification was common in LUAD patients (88/551, 16.0%) and was associated with significantly upregulated UBE2D1 RNA expression. Based on these findings, we infer that UBE2D1 RNA expression might only serve as an independent prognostic indicator of unfavorable OS and RFS in LUAD, but not in LUSC.

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PICOT binding to chromatin-associated EED negatively regulates cyclin D2 expression by increasing H3K27me3 at the CCND2 gene promoter

Cell Death and Disease ◽

10.1038/s41419-019-1935-0 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 2

Author(s):

Pinakin Pandya ◽

Minesh Jethva ◽

Eitan Rubin ◽

Ramon Y. Birnbaum ◽

Alex Braiman ◽

...

Keyword(s):

Target Genes ◽

Patient Survival ◽

Leukemia Cell ◽

Gene Promoter ◽

Human Tumors ◽

Polycomb Group ◽

The Cancer Genome Atlas ◽

Polycomb Group Protein ◽

Cyclin D2 ◽

Human Cancers

Abstract Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT; also termed glutaredoxin 3 (Grx3; Glrx3)) is a ubiquitous protein that can interact with the embryonic ectoderm development (EED) protein via each of its two C-terminal PICOT/Grx homology domains. Since EED is a Polycomb-Group protein and a core component of the polycomb repressive complex 2 (PRC2), we tested the involvement of PICOT in the regulation of PRC2-mediated H3 lysine 27 trimethylation (H3K27me3), transcription and translation of selected PRC2 target genes. A fraction of the cellular PICOT protein was found in the nuclei of leukemia cell lines, where it was associated with the chromatin. In addition, PICOT coimmunoprecipitated with chromatin-residing EED derived from Jurkat and COS-7 cell nuclei. PICOT knockdown led to a reduced H3K27me3 mark and a decrease in EED and EZH2 at the CCND2 gene promoter. In agreement, PICOT-deficient T cells exhibited a significant increase in CCND2 mRNA and protein expression. Since elevated expression levels of PICOT were reported in several different tumors and correlated in the current studies with decreased transcription and translation of the CCND2 gene, we tested whether this opposite correlation exists in human cancers. Data from the Cancer Genome Atlas (TCGA) database indicated statistically significant negative correlation between PICOT and CCND2 in eight different human tumors where the highest correlation was in lung (p = 8.67E−10) and pancreatic (p = 1.06E−5) adenocarcinoma. Furthermore, high expression of PICOT and low expression of CCND2 correlated with poor patient survival in five different types of human tumors. The results suggest that PICOT binding to chromatin-associated EED modulates the H3K27me3 level at the CCND2 gene promoter which may be one of the potential mechanisms for regulation of cyclin D2 expression in tumors. These findings also indicate that a low PICOT/CCND2 expression ratio might serve as a good predictor of patient survival in selected human cancers.

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Circulating miR-16-5p, miR-92a-3p, and miR-451a in Plasma from Lung Cancer Patients: Potential Application in Early Detection and a Regulatory Role in Tumorigenesis Pathways

Cancers ◽

10.3390/cancers12082071 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2071 ◽

Cited By ~ 2

Author(s):

Patricia P. Reis ◽

Sandra A. Drigo ◽

Robson F. Carvalho ◽

Rainer Marco Lopez Lapa ◽

Tainara F. Felix ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Target Genes ◽

Lung Squamous Cell Carcinoma ◽

High Specificity ◽

Mirna Signature ◽

Lung Tumorigenesis ◽

Lung Cancer Patients

Background: Micro(mi)RNAs, potent gene expression regulators associated with tumorigenesis, are stable, abundant circulating molecules, and detectable in plasma. Thus, miRNAs could potentially be useful in early lung cancer detection. We aimed to identify circulating miRNA signatures in plasma from patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and to verify whether miRNAs regulate lung oncogenesis pathways. Methods: RNA isolated from 139 plasma samples (40 LUAD, 38 LUSC; 61 healthy/non-diseased individuals) were divided into discovery (38 patients; 21 controls for expression quantification using an 800-miRNA panel; Nanostring nCounter®) and validation (40 patients; 40 controls; TaqMan® RT-qPCR) cohorts. Elastic net, Maximizing-R-Square Analysis (MARSA), and C-Statistics were applied for miRNA signature identification. Results: When compared to healthy individuals, 580 of 606 deregulated miRNAs in LUAD and 221 of 226 deregulated miRNAs in LUSC had significantly increased levels. Among the 10 most significantly overexpressed miRNAs, 6 were common to patients with LUAD and LUSC. Further analysis identified three signatures composed of 12 miRNAs. Signatures included miRNAs commonly overexpressed in patient plasma. Enriched pathways included target genes modulated by three miRNAs in the C-Statistics signature: miR-16-5p, miR-92a-3p, and miR-451a. Conclusions: The 3-miRNA signature (miR-16-5p, miR-92a-3p, miR-451a) had high specificity (100%) and sensitivity (84%) to predict cancer (LUAD and LUSC). These miRNAs are predicted to modulate genes and pathways with known roles in lung tumorigenesis, including EGFR, K-RAS, and PI3K/AKT signaling, suggesting that the 3-miRNA signature is biologically relevant in adenocarcinoma and squamous cell carcinoma of the lung.

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Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

Cancers ◽

10.3390/cancers12010253 ◽

2020 ◽

Vol 12 (1) ◽

pp. 253 ◽

Cited By ~ 6

Author(s):

Martin A. Prusinkiewicz ◽

Steven F. Gameiro ◽

Farhad Ghasemi ◽

Mackenzie J. Dodge ◽

Peter Y. F. Zeng ◽

...

Keyword(s):

Human Papillomavirus ◽

Head And Neck ◽

Patient Survival ◽

Tricarboxylic Acid Cycle ◽

Predictive Biomarkers ◽

Head And Neck Cancers ◽

The Cancer Genome Atlas ◽

Metabolic Genes ◽

Hpv Status ◽

The Impact

Human papillomavirus (HPV) causes an increasing number of head and neck squamous cell carcinomas (HNSCCs). Altered metabolism contributes to patient prognosis, but the impact of HPV status on HNSCC metabolism remains relatively uncharacterized. We hypothesize that metabolism-related gene expression differences unique to HPV-positive HNSCC influences patient survival. The Cancer Genome Atlas RNA-seq data from primary HNSCC patient samples were categorized as 73 HPV-positive, 442 HPV-negative, and 43 normal-adjacent control tissues. We analyzed 229 metabolic genes and identified numerous differentially expressed genes between HPV-positive and negative HNSCC patients. HPV-positive carcinomas exhibited lower expression levels of genes involved in glycolysis and higher levels of genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, and β-oxidation than the HPV-negative carcinomas. Importantly, reduced expression of the metabolism-related genes SDHC, COX7A1, COX16, COX17, ELOVL6, GOT2, and SLC16A2 were correlated with improved patient survival only in the HPV-positive group. This work suggests that specific transcriptional alterations in metabolic genes may serve as predictive biomarkers of patient outcome and identifies potential targets for novel therapeutic intervention in HPV-positive head and neck cancers.

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Expression of Periostin in Patients with Non-Small Cell Lung Cancer: Correlation with Angiogenesis and Lymphangiogenesis

The International Journal of Biological Markers ◽

10.1177/172460080802300308 ◽

2008 ◽

Vol 23 (3) ◽

pp. 182-186 ◽

Cited By ~ 27

Author(s):

I. Takanami ◽

T. Abiko ◽

S. Koizumi

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Microvessel Density ◽

Survival Rates ◽

Additive Model ◽

Small Cell ◽

Disease Stage ◽

Small Cell Lung ◽

Lymphatic Microvessel Density

The aim of this study was to evaluate periostin expression measured immunohistochemically in patients with non-small cell lung cancer (NSCLC) and to determine its association with clinical features, prognosis, angiogenesis, and lymphangiogenesis. We investigated periostin expression in a series of 88 patients with NSCLC. We also determined whether expression of periostin correlated with microvessel density and lymphatic microvessel density. Periostin was expressed in 42% of 88 patients. Its expression was significantly correlated with tumor size, lymph node metastasis, disease stage, and lymphatic invasion (p=0.0128, 0.0015, 0.0310 and 0.0273, respectively). There also was a significant relation between periostin expression and microvessel density and lymphatic microvessel density (all p<0.0001). Five-year survival rates were better in patients with negative periostin expression than in those with positive periostin expression (p=0.0044). Periostin expression was not significant in a multivariate additive model. Our findings show that periostin correlates with increased tumor progression and a worse prognosis in NSCLC, as well as with angiogenesis and lymphangiogenesis.

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The Expression and Prognostic Role of Peroxiredoxins in Lung Cancer

10.20944/preprints201908.0193.v1 ◽

2019 ◽

Author(s):

Ben Li ◽

Bo Zhang ◽

Qiong Wu ◽

Xinming Chen ◽

Xiang Cao ◽

...

Keyword(s):

Lung Cancer ◽

Lung Squamous Cell Carcinoma ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Expression Level ◽

Normal Lung ◽

Lung Cells ◽

Analysis Tool

Background: Peroxiredoxins (Prxs) comprise antioxidant factors that are widely found in prokaryotes and eukaryotes. Abnormal expression of Prxs is closely related to tumorigenesis. Methods: This study examined the prognostic value and expression of Prxs in lung cancer by Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan-Meier Plotter, cBioPortal and Functional Enrichment Analysis Tool (FunRich) databases. Results: We found that Prx1/2/3/4/5 were overexpressed in both lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) relative to normal lung cells. However, the expression level of Prx6 was lower in LUAD and higher in LUSC than normal lung cells. The level of Prx3 and Prx6 were associated with pathological stage. Prognostic analysis showed that elevated Prx1 and Prx2 expression were correlated with low Overall Survival (OS), whereas high Prx5 and Prx6 expression level predicted high OS. Conclusions: Our results effectively revealed the level of Prxs in lung cancer and its influence on the prognosis of lung carcinoma, contributing to the study of the role of Prxs in tumorigenesis.

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Histone methyltransferase SETD1A participates in lung cancer progression

10.21203/rs.3.rs-66780/v2 ◽

2020 ◽

Author(s):

Mei Du ◽

Piping Gong ◽

Yun Zhang ◽

Yanguo Liu ◽

Xiaozhen Liu ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Normal Lung ◽

Control Group ◽

Cancer Tissue ◽

Mesenchymal Transition ◽

Cancer Symptoms ◽

Mechanistic Analysis

Abstract Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5-year survival rates are lower than ~15%, which is attributes to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome-related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial-mesenchymal transition (EMT), as evidenced by inhibited WNT and TGFβ pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

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A Comprehensive Network Pharmacology-Based Strategy to Investigate Multiple Mechanisms of HeChan Tablet on Lung Cancer

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7658342 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17 ◽

Cited By ~ 2

Author(s):

Zhenjie Zhuang ◽

Qianying Chen ◽

Cihui Huang ◽

Junmao Wen ◽

Haifu Huang ◽

...

Keyword(s):

Lung Cancer ◽

Therapeutic Target ◽

Molecular Mechanisms ◽

Target Genes ◽

Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Network Pharmacology ◽

Hub Genes ◽

Lung Cancer Patients ◽

Ppi Networks

Background. HeChan tablet (HCT) is a traditional Chinese medicine preparation extensively prescribed to treat lung cancer in China. However, the pharmacological mechanisms of HCT on lung cancer remain to be elucidated. Methods. A comprehensive network pharmacology-based strategy was conducted to explore underlying mechanisms of HCT on lung cancer. Putative targets and compounds of HCT were retrieved from TCMSP and BATMAN-TCM databases; related genes of lung cancer were retrieved from OMIM and DisGeNET databases; known therapeutic target genes of lung cancer were retrieved from TTD and DrugBank databases; PPI networks among target genes were constructed to filter hub genes by STRING. Furthermore, the pathway and GO enrichment analysis of hub genes was performed by clusterProfiler, and the clinical significance of hub genes was identified by The Cancer Genome Atlas. Result. A total of 206 compounds and 2,433 target genes of HCT were obtained. 5,317 related genes of lung cancer and 77 known therapeutic target genes of lung cancer were identified. 507 unique target genes were identified among HCT-related genes of lung cancer and 34 unique target genes were identified among HCT-known therapeutic target genes of lung cancer. By PPI networks, 11 target genes AKT1, TP53, MAPK8, JUN, EGFR, TNF, INS, IL-6, MYC, VEGFA, and MAPK1 were identified as major hub genes. IL-6, JUN, EGFR, and MYC were shown to associate with the survival of lung cancer patients. Five compounds of HCT， quercetin, luteolin, kaempferol, beta-sitosterol, and baicalein were recognized as key compounds of HCT on lung cancer. The gene enrichment analysis implied that HCT probably benefitted patients with lung cancer by modulating the MAPK and PI3K-Akt pathways. Conclusion. This study predicted pharmacological and molecular mechanisms of HCT against lung cancer and could pave the way for further experimental research and clinical application of HCT.

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Interobserver Agreement and Assay Reproducibility of Folate Receptor α Expression in Lung Adenocarcinoma: A Prognostic Marker and Potential Therapeutic Target

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2013-0039-oa ◽

2013 ◽

Vol 137 (12) ◽

pp. 1747-1752 ◽

Cited By ~ 15

Author(s):

Ryan E. Bremer ◽

Tatiana S. Scoggin ◽

Elizabeth B. Somers ◽

Daniel J. O'Shannessy ◽

David E. Tacha

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Targeted Therapies ◽

Interobserver Agreement ◽

Folate Receptor ◽

Lung Squamous Cell Carcinoma ◽

Predictive Biomarkers ◽

Predictive Marker ◽

The United States ◽

Scoring Method

Context.—Lung cancer is the leading cause of cancer deaths in the United States and globally. Folate-targeted drugs are among the promising new targeted therapies for lung cancer, provided predictive biomarkers can be identified for optimal patient selection. Objective.—To evaluate the interobserver agreement and reproducibility of an immunohistochemistry assay for folate receptor α as a potential predictive marker for folate-targeted therapies. Design.—Immunohistochemistry using anti–folate receptor α antibody 26B3 was performed on formalin-fixed, paraffin-embedded tissues. The M-score, a semiquantitative measure of staining intensity and proportion of tumor cells staining, was determined for each specimen. Interobserver agreement was assessed using lung adenocarcinoma specimens stained at a single site and evaluated by 3 independent pathologists. Interinstrument reproducibility assessed 20 specimens stained by 3 different automated stainers. Interlaboratory agreement was determined on 5 specimens, repeatedly stained on each of 5 days, at 3 different study sites. Results.—Folate receptor α expression was identified in 39 of 54 cases of lung adenocarcinoma (72%) and 4 of 37 cases of lung squamous cell carcinoma (11%). Agreement among 3 pathologists was found in 24 of 26 cases (92%). Interinstrument reproducibility was observed in 19 of 20 cases (95%). Agreement among 3 laboratories was found for 49 of 50 specimens (98%). Conclusions.—Immunostaining of folate receptor α in lung adenocarcinomas is reproducible across staining platforms and among laboratories. Agreement among pathologists is achieved using a semiquantitative scoring method. An accurate and convenient method for determining folate receptor α expression offers a potentially invaluable tool for selecting patients for folate-targeted therapies.

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