Transcriptional Profiling Reveals the Regulatory Role of DNER in Promoting Pancreatic Neuroendocrine Neoplasms.

Rui He,Wenbin Yang,Junhui Li,Yang Liu,Wunai Zhang,Shuo Chen

doi:10.3389/fgene.2020.587402

Abstract

Wnt/β-catenin and NOTCH signaling contribute to the pathogenesis and growth of (PanNENs). The wnt and Notch signaling pathways form an integrated signaling device termed “wntch” and regulate stochastic cell fate decisions, suggesting the essentiality of Wnt/Notch interactions in disease progression. However, the function of Wnt/Notch interactions in PanNENs is unclear. We analyzed RNA sequencing (RNA-seq) data to identify differentially expressed lncRNAs, mRNAs and pathways according to enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PanNENs. RNA-seq analysis revealed that the levels of the lncRNA XLOC_221242 and the mRNA encoding Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) were significantly increased in tumor tissues compared with normal tissues (n = 3). Protein-protein interaction (PPI) prediction combined with transcriptional profiling data analysis revealed that DNER expression levels were positively correlated with those of DNA-binding factor (RBPJ), S phase kinase-associated protein 1 (Skp1), CTNNB1 and Cadherin-2 (CDH2), which promote PanNEN tumorigenesis and progression. These results were consistent with those of immunohistochemical analysis of DNER, RBPJ, SKP1, CTNNB1, and CDH2 expression (n = 15). These findings provide compelling clinical and molecular evidence supporting the conclusion that DNER and the related RBPJ, SKP1, CTNNB1, and CDH2 signaling contribute to PanNEN tumorigenesis and progression by activating wnt/Notch interactions.

Highlights

The incidence of pancreatic neuroendocrine neoplasms (PanNENs), which account for only 1–2% of all pancreatic malignancies, is increasing (Anderson and Bennett, 2016)
This study aimed to identify the long noncoding RNA (lncRNA) and mRNA expression profiles and explore the lncRNA-mRNA coexpression networks associated with PanNEN tumorigenesis
2http://www.bioconductor.org/packages/release/bioc/html/clusterProfiler.html with the matched paratumor tissues and may be involved in we found that DNER signaling pathway participating in many the DNER signaling pathway in PanNENs (Supplementary processes of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, including Figure 3A)

Summary

Introduction

The incidence of pancreatic neuroendocrine neoplasms (PanNENs), which account for only 1–2% of all pancreatic malignancies, is increasing (Anderson and Bennett, 2016). The treatment, curative surgery and systemic medication, is dependent on various factors to improve the survival outcome of patients with PanNENs (Ishida and Lam, 2020). The survival of patients with PanNENs has improved over time, but some factors, including G stage, surgical resection margin, lymph node, TMN stage, metastasis, the necrosis and vascular invasion (Gao Y. et al, 2018). PanNENs are benign, some can progress to metastasis, depending on their size, functional status, and grade (Fang and Shi, 2019). Via whole-exome sequencing, MEN1 inactivation, DAXX/ATRX mutation and/or loss, and mutations in mammalian target of rapamycin (mTOR) pathway genes, MUTYH, CHECK2, and BRCA2 were found to be related to the tumorigenesis of PanNENs (Vinik et al, 2000; Chai et al, 2018). High expression of either of two lncRNAs—MALAT1 or HOTAIR— was reported to be negatively associated with characteristics of lower aggressiveness, including lower T stage and less frequent development of metastases, independent of histologic grade (Chu et al, 2019)

Objectives

Methods

Results

Discussion

Conclusion