Bioinformatic Analysis and Integration of Transcriptome and Proteome Results Identify Key Coding and Noncoding Genes Predicting Malignancy in Intraductal Papillary Mucinous Neoplasms of the Pancreas

Abstract

Background. Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic ductal adenocarcinoma (PDAC). IPMNs are generally associated with high risk of developing malignancy and therefore need to be diagnosed and assessed accurately, once detected. Existing diagnostic methods are inadequate, and identification of efficient biomarker capable of detecting high-risk IPMNs is necessitated. Moreover, the mechanism of development of malignancy in IPMNs is also elusive. Methods. Gene expression meta-analysis conducted using 12 low-risk IPMN and 23 high-risk IPMN tissue samples. We have also listed all the altered miRNAs and long noncoding RNAs (lncRNAs), identified their target genes, and performed pathway analysis. We further enlisted cyst fluid proteins detected to be altered in high-risk or malignant IPMNs and compared them with fraction of differentially expressed genes secreted into cyst fluid. Results. Our meta-analysis identified 270 upregulated and 161 downregulated genes characteristically altered in high-risk IPMNs. We further identified 61 miRNAs and 14 lncRNAs and their target genes and key pathways contributing towards understanding of the gene regulation during the progression of the disease. Most importantly, we have detected 12 genes altered significantly both in cystic lesions and cyst fluid. Conclusion. Our study reports, for the first time, a meta-analysis identifying key changes in gene expression between low-risk and high-risk IPMNs and also explains the regulatory aspect through construction of a miRNA-lncRNA-mRNA interaction network. The 12-gene-signature could function as potential biomarker in cyst fluid for detection of IPMN with a high risk of developing malignancy.

Identification of hsa-miR-4770 as characteristic microRNA of gallbladder carcinoma and exploration on the ceRNA regulation mechanism via integrated bioinformatics analysis

“…Elena Vila Navarro et al [32] sequenced and validated the miRNAs used to detect pancreatic tumors and found that hsa-miR-4770 was signi cantly upregulated in pancreatic ductal adenocarcinoma, and identi ed hsa-miR-4770 as one of the novel markers with potential diagnostic or therapeutic value. In addition, hsa-miR-4770 was upregulated in pancreatic intraductal papillary mucinous neoplasms [33]. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is overexpressed in malignant retinoblastoma (RB), the ceRNA network was constructed between MALAT1 and cytokinesis-associated genes, and hsa-miR-4770 was found as one of the potential miRNAs involved in the association of MALAT1 and RB [34].…”

Emerging role of non-invasive and liquid biopsy biomarkers in pancreatic cancer

“…Some reports found tumor-specific upregulation of various types of small noncoding RNAs (ncRNAs), such as small nuclear RNAs, Piwi-interacting RNAs and long ncRNAs (lncRNAs) like HOTAIR and MALAT1. They act as diagnostic and prognostic markers in the serum or plasma of cancer patients[ 84 , 85 ]. Amidst that, some have reported alterations in gene expression according to disease progression, which discriminates between a chronic inflammatory state and carcinoma (Table 3 )[ 86 , 87 ].…”

Modern aspects of the management of pancreatic intraductal papillary mucinous neoplasms: a narrative review

“…There were key changes in gene expression between low-risk and high-risk IPMNs. However, 12 genes were altered significantly, and the so-called “12-gene signature” has been proposed as a potential biomarker in the pancreatic juice for the identification of IPMNs that have a high risk for malignant development [ 26 ]. The key signaling pathways or protein complexes involved in the pathogenesis of IPMNs include G-protein-coupled receptor (GPCR), transforming growth factor (TGF), SWI/SNF, WNT and phosphatidylinositol 3-kinase (PI3K) [ 27 ].…”

“…There were key changes in gene expression between low-risk and high-risk IPMNs. However, 12 genes were altered significantly, and the so-called "12-gene signature" has been proposed as a potential biomarker in the pancreatic juice for the identification of IPMNs that have a high risk for malignant development [26].…”