Identification of key lncRNAs in the tumorigenesis of intraductal pancreatic mucinous neoplasm by coexpression network analysis.

Intraductal papillary mucinous neoplasm (IPMN) is an intraepithelial precancerous lesion of pancreatic ductal adenocarcinoma (PDAC) that progresses from adenoma to carcinoma, and long noncoding RNAs (lncRNA) might be involved in the tumorigenesis. In this study, we obtained the expression profiles of more than 4000 lncRNAs by probe reannotation of a microarray dataset. As a correlation network-based systems biology method, weighted gene coexpression network analysis (WGCNA) was used to find clusters of highly correlated lncRNAs in the tumorigenesis of IPMN, which covered four stepwise stages from normal main pancreatic duct to invasive IPMN. In the most relevant module (R  = -0.75 and P = 5E-05), three hub lncRNAs were identified (HAND2-AS1, CTD-2033D15.2, and lncRNA-TFG). HAND2-AS1 and CTD-2033D15.2 were negatively correlated with the tumorigenesis (P in one-way ANOVA test = 1.45E-07 and 1.39E-0.5), while lncRNA-TFG were positively correlated with the tumorigenesis (P = 3.99E-08). The validation set reached consistent results (P = 2.66E-03 in HAND2-AS1, 1.47E-04 in CTD-2033D15.2 and 6.23E-08 in lncRNA-TFG). In functional enrichment analysis, the target genes of microRNAs targeting also these lncRNAs were overlapped in multiple biological processes, pathways and malignant diseases including pancreatic cancer. In survival analysis, patients with higher expression of HAND2-AS1-targeted and CTD-2033D15.2-targeted microRNAs showed a significantly poorer prognosis in PDAC, while high expression of lncRNA-TFG-targeted microRNAs demonstrated an obviously better prognosis (log-rank P < .05). In conclusion, by coexpression network analysis of the lncRNA profiles, three key lncRNAs were identified in association with the tumorigenesis of IPMN, and those lncRNAs might act as early diagnostic biomarkers or therapeutic targets in pancreatic cancer.