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Analysis of distinct long noncoding RNA transcriptional fingerprints in pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies with the worst prognosis. Recent studies have demonstrated that long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis and cancer progression. However, the expression pattern and roles of lncRNAs in the development of PDAC remain unknown. Herein, we globally analyzed the lncRNA expression profile in human PDAC and non-tumor tissues using four independent public microarray datasets from Gene Expression Omnibus (GEO). The analysis of GEO datasets by repurposing microarray probes confirmed that hundreds of lncRNAs are differentially expressed in PDAC tissues compared with normal tissues. We selected four lncRNAs including LINC00152, CASC9, LINC00226 and F11-AS1 for validation in PDAC cell lines and normal cells. Loss of function assays were performed to investigate the roles of LINC00152 and CASC9 in PDAC cell proliferation and invasion. Taken together, our findings demonstrate lncRNA expression alterations in PDAC and may provide new potential molecular markers for PDAC patient diagnosis and treatment.

SUBMITTER: Yu X

PROVIDER: S-EPMC5345666 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Analysis of distinct long noncoding RNA transcriptional fingerprints in pancreatic ductal adenocarcinoma.

Yu Xiang X Lin Yang Y Sui Wu W Zou Yanfen Y Lv Zhongchuan Z

Cancer medicine 20170221 3

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies with the worst prognosis. Recent studies have demonstrated that long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis and cancer progression. However, the expression pattern and roles of lncRNAs in the development of PDAC remain unknown. Herein, we globally analyzed the lncRNA expression profile in human PDAC and non-tumor tissues using four independent public microarray datasets from Gene ...[more]

PMID: 28220683

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Project description:BACKGROUND:Long noncoding RNAs have been shown to play crucial roles in cancer biology, while the long noncoding RNA landscapes of pancreatic ductal adenocarcinoma have not been completely characterized. We aimed to determine whether long noncoding RNA could serve as early diagnostic biomarkers for pancreatic ductal adenocarcinoma. METHOD:We conducted a genome-wide microarray analysis on pancreatic ductal adenocarcinoma and their adjacent noncancerous tissues from 8 Chinese patients. RESULTS:A total of 3352 significantly differentially expressed long noncoding RNAs were detected. Of total, 1249 long noncoding RNAs were upregulated and 2103 were downregulated (fold change ?2, P < 0.05, FDR <0.05). These differentially expressed long noncoding RNAs were not evenly distributed among chromosomes in human genome. Hierarchical clustering of these differentially expressed long noncoding RNAs revealed large variabilities in long noncoding RNA expression among individual patient, indicating that certain long noncoding RNAs could play a unique role or be used as a biomarker for specific subtype of pancreatic ductal adenocarcinoma. Gene Ontology enrichment and pathway analysis identified several remarkably dysregulated pathways in pancreatic ductal adenocarcinoma tissue, such as interferon-?-mediated signaling pathway, mitotic cell cycle and proliferation, extracellular matrix receptor interaction, focal adhesion, and regulation of actin cytoskeleton. The co-expression network analysis detected 393 potential interactions between 80 differentially expressed long noncoding RNAs and 105 messenger RNAs. We experimentally verified 7 most markedly dysregulated long noncoding RNAs from the network. CONCLUSION:Our study provided a genome-wide survey of dysregulated long noncoding RNAs and long noncoding RNA/messenger RNA co-regulation networks in pancreatic ductal adenocarcinoma tissue. These dysregulated long noncoding RNA/messenger RNA networks could be used as biomarkers to provide early diagnosis of pancreatic ductal adenocarcinoma or its subtype, predict prognosis, and evaluate treatment efficacy.

Project description:Previous studies have shown that forkhead box P4 antisense RNA 1 (FOXP4-AS1) is dysregulated in tumor tissues and can serve as a prognostic indicator for multiple cancers. However, the clinical significance of FOXP4-AS1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The goal of this study is to recognize the possible clinical significance of long noncoding RNA FOXP4-AS1 in patients with early stage PDAC. A total of 112 patients from The Cancer Genome Atlas (TCGA) PDAC cohort, receiving RNA sequencing, were involved in the study. Survival analysis, functional mechanism, and potential small molecule drugs of target therapy of FOXP4-AS1 were performed in this study. Survival analysis in TCGA PDAC cohort suggested that patients with high FOXP4-AS1 expression had significantly augmented possibility of death than in PDAC patients with lower FOXP4-AS1 expression (adjusted P = .008; adjusted HR = 2.143, 95% CI = 1.221-3.760). In this study, a genome-wide RNA sequencing dataset was used to identify 927 genes co-expressing with FOXP4-AS1 in PDAC tumor tissues. A total of 676 differentially expressed genes were identified between different FOXP4-AS1 expression groups. Functional enrichment analysis of these genes and gene set enrichment analysis for PDAC genome-wide RNA sequencing dataset was done. We have found that FOXP4-AS1 may function in PDAC by participating in biological processes and pathways including oxidative phosphorylation, tricarboxylic acid cycle, classical tumor-related pathways such as NF-kappaB as well as Janus kinase/signal transducers in addition to activators of transcription, cell proliferation, and adhesion. In addition, we also screened two potential targeted therapeutic small molecule drugs (dimenhydrinate and metanephrine) for FOXP4-AS1 in PDAC. In conclusion, our present study demonstrated that higher expression of FOXP4-AS1 in PDAC tumor tissues were related with an inferior medical outcome. Through multiple genome-wide approaches, we identified the potential molecular mechanisms of FOXP4-AS1 in PDAC and two targeted therapeutic drugs for it.

Dataset Information

Analysis of distinct long noncoding RNA transcriptional fingerprints in pancreatic ductal adenocarcinoma.

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Analysis of distinct long noncoding RNA transcriptional fingerprints in pancreatic ductal adenocarcinoma.

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