Construction and analysis of dysregulated lncRNA-associated ceRNA network identified novel lncRNA biomarkers for early diagnosis of human pancreatic cancer

// Meng Zhou 1, * , Zhiyong Diao 2, * , Xiaolong Yue 3, * , Yang Chen 1 , Hengqiang Zhao 1 , Liang Cheng 1 , Jie Sun 1 1 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, PR China 2 Department of Plastic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China 3 Medical Oncology Department, Affiliated Tumor Hospital, Harbin Medical University, Harbin, 150001, PR China * These authors contributed equally to this work Correspondence to: Jie Sun, email: suncarajie@hotmail.com Liang Cheng, email: liangcheng@hrbmu.edu.cn Keywords: competing endogenous RNAs, ceRNA network, early diagnosis, long non-coding RNAs, pancreatic cancer Received: June 21, 2016      Accepted: July 19, 2016      Published: July 28, 2016 ABSTRACT It is increasing evidence that ceRNA activity of long non-coding RNAs (lncRNAs) played critical roles in both normal physiology and tumorigenesis. However, functional roles and regulatory mechanisms of lncRNAs as ceRNAs in pancreatic ductal adenocarcinoma (PDAC), and their potential implications for early diagnosis remain unclear. In this study, we performed a genome-wide analysis to investigate potential lncRNA-mediated ceRNA interplay based on “ceRNA hypothesis”. A dysregulated lncRNA-associated ceRNA network (DLCN) was constructed by utilizing sample-matched miRNA, lncRNA and mRNA expression profiles in PDAC and normal samples in combination with miRNA regulatory network. The results of network analysis uncovered seven novel lncRNAs as functional ceRNAs whose aberrant expression will result in the extensive variation in tumorigenic or tumor-suppressive gene expression through DLCN at the post-transcriptional level contributing to PDAC. Therefore, we developed a 7-lncRNA signature (termed LncRisk-7) based on the expression data of seven lncRNAs and SVM algorithm as a novel diagnostic tool to improve early diagnosis of PDAC. The LncRisk-7 achieved high performance in distinguishing PDAC patients from nonmalignant pancreas samples in the discovery cohort and was further confirmed in another two independent validation cohorts. Functional analysis demonstrated that seven lncRNA biomarkers act as ceRNAs involving the regulation of cell death, cell adhesion and cell cycle. This study will help to improve our understanding of the lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of PDAC and provide novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets.