Circulating Extracellular Vesicle-Encapsulated HULC Is a Potential Biomarker for Human Pancreatic Cancer

Abstract

Background: The role of long non-coding RNAs (lncRNAs) in the epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) is unclear. Some lncRNAs can be transferred by extracellular vesicles (EVs) and have potential as biomarkers. Here, we identify a lncRNA that could serve as a biomarker for PDAC and show the functional roles of the lncRNA during the EMT. Methods: Human PDAC cells and PDAC cell xenografts in nude mice were used to assess the roles of lncRNAs and microRNAs (miRNAs) for PDAC development. Serum samples were obtained from PDAC patients, intraductal papillary mucinous neoplasm (IPMN) patients, and healthy individuals to analyze EV lncRNA expression by digital PCR. Findings: Expression profiling of lncRNAs revealed that HULC was highly expressed, and induced, by transforming growth factor β in PDAC cells and their EVs. HULC knockdown decreased cell invasion and migration by inhibiting the EMT. HULC could be transferred by EVs, and promoted the EMT, invasion, and migration in recipient PDAC cells. HULC knockdown in PDAC cells implanted in mice inhibited tumor growth. Moreover, miR-133b suppressed the EMT via targeting HULC. In serum EVs, HULC expression was significantly increased in PDAC patients compared to healthy individuals or IPMN patients. HULC showed good predictive performance for discriminating PDAC. Interpretation: EV transported HULC promotes cell invasion and migration by inducing the EMT, and miR-133b suppresses the EMT by targeting HULC. EV-encapsulated HULC could be a potential circulating biomarker for human PDAC. Funding: This project was supported by JSPS KAKENHI Grant Number JP15K19303. Declaration of Interest: The authors have no conflict of interest to disclose. Ethical Approval: All animals received humane care and studies were performed under an institutionally approved animal care protocol. Human studies were approved by the Asahikawa Medical University Institutional Review Board (protocol number 15084), and informed consent was obtained from all subjects.