1
|
Agrawal P, Olgun G, Singh A, Gopalan V, Hannenhalli S. Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers. Comput Struct Biotechnol J 2024; 27:252-264. [PMID: 39866667 PMCID: PMC11763893 DOI: 10.1016/j.csbj.2024.12.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/28/2025] Open
Abstract
Exosomal microRNAs (exomiRs) play a critical role in intercellular communication, especially in cancer, where they regulate key cellular processes like proliferation, angiogenesis, and metastasis, highlighting their significance as potential diagnostic and therapeutic targets. Here, we aimed to characterize the role of exomiRs, derived from seven cancer types (four cell lines and three tumors), in influencing the pre-metastatic niche (PMN). In each cancer type we extracted high confidence exomiRs (LogFC >= 2 in exosomes relative to control), their experimentally validated targets, and the enriched pathways among those targets. We then selected the top100 high-confidence targets based on their frequency of appearance in the enriched pathways. We observed significantly higher GC content in exomiRs relative to genomic background. Gene Ontology analysis revealed both general cancer processes, such as wound healing and epithelial cell proliferation, as well as cancer-specific processes, such as "angiogenesis" in the kidney and "ossification" in the lung. ExomiR targets were enriched for cancer-specific tumor suppressor genes and downregulated in PMN formed in lungs compared to normal. Motif analysis showed high inter-cancer similarity among motifs enriched in exomiRs. Our analysis recapitulated exomiRs associated with M2 macrophage differentiation and chemoresistance, such as miR-21 and miR-222-3p, regulating signaling pathways like PTEN/PI3/Akt, NF-kB, etc. Additionally, Cox regression analysis in TCGA indicated that exomiR targets are significantly associated with better overall survival of patients. Lastly, support vector machine model using exomiR targets gene expression classified responders and non-responders to therapy with an AUROC ranging from 0.72 to 0.96, higher than previously reported gene signatures.
Collapse
Affiliation(s)
- Piyush Agrawal
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA
| | - Gulden Olgun
- Department of Computer Engineering, Hacettepe University, Ankara 06800, Turkey
| | - Arashdeep Singh
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA
| | - Vishaka Gopalan
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA
| | - Sridhar Hannenhalli
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA
| |
Collapse
|
2
|
Agrawal P, Olgun G, Singh A, Gopalan V, Hannenhalli S. Characterizing the role of exosomal miRNAs in metastasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.20.608894. [PMID: 39372783 PMCID: PMC11451750 DOI: 10.1101/2024.08.20.608894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Background Exosomal microRNAs (exomiRs), transported via exosomes, play a pivotal role in intercellular communication. In cancer, exomiRs influence tumor progression by regulating key cellular processes such as proliferation, angiogenesis, and metastasis. Their role in mediating communication between cancer cells and the tumor microenvironment highlights their significance as potential diagnostic and therapeutic targets. Methodology In this study, we aimed to characterize the role of exomiRs in influencing the pre-metastatic niche (PMN). Across 7 tumor types, including 4 cell lines and three tumors, we extracted high confidence exomiRs (Log FC >= 2 in exosomes relative to control) and their targets (experimentally identified and targeted by at least 2 exomiRs). Subsequently, we identified enriched pathways and selected the top 100 high-confidence exomiR targets based on the frequency of their appearance in the enriched pathways. These top 100 targets were consistently used throughout the analysis. Results Cancer cell line and tumor derived ExomiRs have significantly higher GC content relative to genomic background. Pathway enriched among the top exomiR targets included general cancer-associated processes such as "wound healing" and "regulation of epithelial cell proliferation", as well as cancer-specific processes, such as "regulation of angiogenesis in kidney" (KIRC), "ossification" in lung (LUAD), and "positive regulation of cytokine production" in pancreatic cancer (PAAD). Similarly, 'Pathways in cancer' and 'MicroRNAs in cancer' ranked among the top 10 enriched KEGG pathways in all cancer types. ExomiR targets were not only enriched for cancer-specific tumor suppressor genes (TSG) but are also downregulated in pre-metastatic niche formed in lungs compared to normal lung. Motif analysis shows high similarity among motifs identified from exomiRs across cancer types. Our analysis recapitulates exomiRs associated with M2 macrophage differentiation and chemoresistance such as miR-21 and miR-222-3p, regulating signaling pathways such as PTEN/PI3/Akt, NF-κB, etc. Cox regression indicated that exomiR targets are significantly associated with overall survival of patients in TCGA. Lastly, a Support Vector Machine (SVM) model using exomiR target gene expression classified responders and non-responders to neoadjuvant chemotherapy with an AUROC of 0.96 (in LUAD), higher than other previously reported gene signatures. Conclusion Our study characterizes the pivotal role of exomiRs in shaping the PMN in diverse cancers, underscoring their diagnostic and therapeutic potential.
Collapse
Affiliation(s)
- Piyush Agrawal
- Department of Medical Research, SRM Medical College Hospital & Research Centre, SRMIST, Kattankulathur, Chennai, Tamil Nadu, India
| | - Gulden Olgun
- Department of Computer Engineering, Hacettepe University, 06800, Ankara, Turkey
| | - Arashdeep Singh
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA
| | - Vishaka Gopalan
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA
| | - Sridhar Hannenhalli
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA
| |
Collapse
|
3
|
Hasib FY. Esophageal squamous cell carcinoma: Integrated bioinformatics analysis for differential gene expression with identification of hub genes and lncRNA. Biochem Biophys Rep 2022; 30:101262. [PMID: 35479061 PMCID: PMC9035652 DOI: 10.1016/j.bbrep.2022.101262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/09/2022] Open
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is a typical Gastro-Intestinal (GI) tract neoplasm. This study was conducted to know the Differential Expressed Genes (DEGs) profile of ESCC along with hub gene screening, lncRNA identification, and drug-genes interactions. Methods GSE161533, GSE20347, GSE45670 microarray datasets were retrieved from the NCBI Gene Expression Omnibus (GEO) database. GEO2R was used for the DEGs identification, whereas GO (Gene Ontology) and KEGG enrichment analysis were performed in DAVID. PPI network constructed using STRING and visualized with Cytoscape app with the help of MCODE. The top ten connectivity genes were selected as hub genes—further survival analysis was performed in the Kaplan-Meier plotter. Moreover, Boxplot, pathological stage plots were constructed using GEPIA (Gene Expression Profiling Interactive Analysis). The methylation heatmap assembled in the DiseaseMeth version 2.0. lncRNA (Long non-coding RNA) was identified comparing the list of genes in HUGO, and Gene-drug interactions were accumulated from the DgiDB platform. Results This experiment showed 16 upregulated, and 59 downregulated DEGs shared among the three datasets. Biological process analysis showed significant terms such as extracellular matrix disassembly and collagen catabolism. The extracellular region was detected as the most crucial cellular compartment. Notably, metalloen dopeptidease and serine-type endopeptidase activity showed significant molecular functions term. In contrast, transcriptional misregulation was a highly substantial KEGG pathway. Kaplan-Meier plotter showed higher expression of CXCL8, SPP1, MMP13, CXCL1, and TOP2A have a significant impact on the overall survival of the patients. Nine out of ten hub genes have significantly different expression levels than normal and cancer tissues. HYMAI was the only lncRNA commonly expressed upregulated among the three datasets. Drug-gene interaction showed multiple genes have no drug options exist till now.
GSE161533, GSE20347, and GSE45670 microarray datasets were analyzed. 16 upregulated and 59 downregulated DEGs shared among the three datasets. CXCL8, SPP1, MMP13, CXCL1, and TOP2A have a significant impact on survival. HYMAI was the only lncRNA commonly expressed. Multiple genes have no drug options that exist.
Collapse
|
4
|
Murugesan M, Premkumar K. Integrative miRNA-mRNA functional analysis identifies miR-182 as a potential prognostic biomarker in breast cancer. Mol Omics 2021; 17:533-543. [PMID: 33884382 DOI: 10.1039/d0mo00160k] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Breast cancer (BC) is a heterogeneous disease distinct from major clinical hindrances, and microRNAs (miRNAs) have been accounted to partake in BC progression. Identifying potential miRNAs and their pathological significance in BC could pave the way for precisely targeted treatments. This study exploits transcriptomic BC miRNA, mRNA cohorts, and prognostic significance via an integrative functional approach. miRNA transcriptomic cohorts (GSE45666, GSE40267, and GSE19783) were utilized to disseminate differentially expressed miRNAs (DEmiRNAs) and their expression in the clinicopathological variables of BC. miR-182 was identified as a potent candidate, differentially expressed between each BC stage and its adjacent normal samples. The expression of miR-182 was significantly associated with estrogen receptor (ER) (p = 0.052), and closely related to progesterone receptor (PR) (p = 0.061) and human epidermal growth factor receptor 2 (Her2) (p = 0.077). miRNA-mRNA regulatory targets were predicted using six different databases, namely, TargetScan, miRDB, Diana, miRNet, TargetMiner, and miRWalk. Twenty-four promising mRNA regulatory targets were potentially identified for miR-182 and thus highly enriched with cellular metabolic processes, proteoglycans, and focal adhesion pathways in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms. Subsequently, the F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) gene was recognized as a hub with the highest connectivity score in the protein-protein interaction network. Furthermore, miR-182 and FBXW7 were associated with poor prognostic clinical outcomes in BC patients. Thus, our integrated functional analysis suggests that miR-182 might lead to a new therapeutic target in BC manifestation.
Collapse
Affiliation(s)
- Manikandan Murugesan
- Department of Biomedical Science, School of Biotechnology and Genetic Engineering, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.
| | - Kumpati Premkumar
- Department of Biomedical Science, School of Biotechnology and Genetic Engineering, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.
| |
Collapse
|
5
|
RNA methylations in human cancers. Semin Cancer Biol 2020; 75:97-115. [DOI: 10.1016/j.semcancer.2020.11.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/23/2020] [Accepted: 11/08/2020] [Indexed: 12/24/2022]
|
6
|
Identification of candidate aberrantly methylated and differentially expressed genes in Esophageal squamous cell carcinoma. Sci Rep 2020; 10:9735. [PMID: 32546690 PMCID: PMC7297810 DOI: 10.1038/s41598-020-66847-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 05/28/2020] [Indexed: 12/11/2022] Open
Abstract
Aberrant methylated genes (DMGs) play an important role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). In this study, we aimed to integrate three cohorts profile datasets to ascertain aberrant methylated-differentially expressed genes and pathways associated with ESCC by comprehensive bioinformatics analysis. We downloaded data of gene expression microarrays (GSE20347, GSE38129) and gene methylation microarrays (GSE52826) from the Gene Expression Omnibus (GEO) database. Aberrantly differentially expressed genes (DEGs) were obtained by GEO2R tool. The David database was then used to perform Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses on selected genes. STRING and Cytoscape software were used to construct a protein-protein interaction (PPI) network, then the modules in the PPI networks were analyzed with MCODE and the hub genes chose from the PPI networks were verified by Oncomine and TCGA database. In total, 291 hypomethylation-high expression genes and 168 hypermethylation-low expression genes were identified at the screening step, and finally found six mostly changed hub genes including KIF14, CDK1, AURKA, LCN2, TGM1, and DSG1. Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process. After validation in multiple databases, most hub genes remained significant. Patients with high expression of AURKA were associated with shorter overall survival. To summarize, we have identified six feasible aberrant methylated-differentially expressed genes and pathways in ESCC by bioinformatics analysis, potentially providing valuable information for the molecular mechanisms of ESCC. Our data combined the analysis of gene expression profiling microarrays and gene methylation profiling microarrays, simultaneously, and in this way, it can shed a light for screening and diagnosis of ESCC in future.
Collapse
|
7
|
Sang L, Yu Z, Wang A, Li H, Dai X, Sun L, Liu H, Yuan Y. Identification of methylated-differentially expressed genes and pathways in esophageal squamous cell carcinoma. Pathol Res Pract 2020; 216:153050. [PMID: 32825936 PMCID: PMC7283077 DOI: 10.1016/j.prp.2020.153050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/26/2020] [Accepted: 06/07/2020] [Indexed: 12/19/2022]
Abstract
Methylation, as an epigenetic modification, can affect gene expression and play a role in the occurrence and development of cancer. This research is devoted to discover methylated-differentially expressed genes (MDEGs) in esophageal squamous cell carcinoma (ESCC) and explore special associated pathways. We downloaded GSE51287 methylation profiles and GSE26886 expression profiles from GEO DataSets, and performed a comprehensive bioinformatics analysis. Totally, 19 hypermethylated, lowly expressed genes (Hyper-LGs) were identified, and involved in regulation of cell proliferation, phosphorus metabolic process and protein kinase activity. Meanwhile, 17 hypomethylated, highly expressed genes (Hypo-HGs) were participated in collagen catabolic process, metallopeptidase and cytokine activity. Pathway analysis determined that Hyper-LGs were enriched in arachidonic acid metabolism pathway, while Hypo-HGs were primarily associated with the cytokine-cytokine receptor interaction pathway. IL 6, MMP3, MMP9, SPP1 were identified as hub genes based on the PPI network that combined 7 ranked methods included in cytoHubba, and verification was performed in human tissues. Our integrated analysis identified many novel genetic lesions in ESCC and provides a crucial molecular foundation to improve our understanding of ESCC. Hub genes, including IL 6, MMP3, MMP9 and SPP1, could be considered for use as aberrant methylation-based biomarkers to facilitate the accurate diagnosis and therapy of ESCC.
Collapse
Affiliation(s)
- Liang Sang
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Ultrasound Department, the First Hospital of China Medical University, Shenyang 110001, China
| | - Zhanwu Yu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Shenyang, Liaoning 110042, China
| | - Ang Wang
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Hao Li
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Xiantong Dai
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Liping Sun
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Shenyang, Liaoning 110042, China.
| | - Yuan Yuan
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
| |
Collapse
|
8
|
Patowary P, Bhattacharyya DK, Barah P. Identifying critical genes in esophageal squamous cell carcinoma using an ensemble approach. INFORMATICS IN MEDICINE UNLOCKED 2020. [DOI: 10.1016/j.imu.2019.100277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
|
9
|
Hua C, Chen X, Yuan W, Li Y, Yu J, Li H, Ming L. Gene expression profiling by mRNA sequencing reveals dysregulation of core genes in Rictor deficient T-ALL mouse model. Leuk Res 2019; 87:106229. [PMID: 31698306 DOI: 10.1016/j.leukres.2019.106229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 09/09/2019] [Accepted: 09/25/2019] [Indexed: 11/29/2022]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder with peak incidence in children and young adults. The mTOR complex is an important component of the PI3K/Akt/mTOR signaling cascade and holds great promise for the treatment of hematopoietic malignancies. Previous studies have shown that the depression of Rictor, one of the components of the mTOR complex, prevents myeloproliferative disorders and leukemia However, knowledge of the progression of mTOR has not greatly improved the prognosis of T-ALL. To identify potential prognostic biomarkers for T-ALL, a whole-genome expression profile of Rictior deficient T-ALL mice was performed. As a result, 1475 differentially expressed genes (DEGs) were identified. Network analysis revealed 46 genes with a high network degree and fold-change value. Kaplan-Meier analysis identified ten crucial genes which significantly associated with survival in Rictor deficient T-ALL mice. These findings provide potential therapeutic targets in leukemia and bear immediate relevance to patients with leukemia.
Collapse
Affiliation(s)
- Chunlan Hua
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xiangyu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Weiping Yuan
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China
| | - Yang Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Jing Yu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Haijun Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Liang Ming
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
| |
Collapse
|