Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2019; 25(35): 5283-5299
Published online Sep 21, 2019. doi: 10.3748/wjg.v25.i35.5283
Long non-coding RNA highly up-regulated in liver cancer promotes exosome secretion
Shun-Qi Cao, Hong Zheng, Bao-Cun Sun, Zheng-Lu Wang, Tao Liu, Dong-Hui Guo, Zhong-Yang Shen
Shun-Qi Cao, Dong-Hui Guo, Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, China
Hong Zheng, Zhong-Yang Shen, Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, China
Bao-Cun Sun, Department of Pathology, Tianjin Medical University, Tianjin 300070, China
Zheng-Lu Wang, Department of Pathology, Tianjin First Central Hospital, Tianjin 300192, China
Tao Liu, NHC Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300192, China
Author contributions: Cao SQ, Zheng H, Sun BC, Wang ZL, and Liu T performed the research, analysed the data, and wrote and revised the manuscript; Shen ZY designed the study and participated in the revision of the article; all authors have read and approved the final manuscript.
Supported by Tianjin Clinical Research Center for Organ Transplantation Project, No. 15ZXLCSY00070; and The Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, No. 2018PT32021.
Institutional review board statement: The study was reviewed and approved by the Tianjin First Central Hospital Medical Ethics Committee.
Conflict-of-interest statement: The authors declare no potential conflict of interest in this paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Zhong-Yang Shen, MD, PhD, Professor, Department of Organ Transplantation, Tianjin First Central Hospital, No. 24, Fukang Road, Nankai District, Tianjin 300192, China. shen_zhongyang@126.com
Telephone: +86-22-2362698 Fax: +86-22-2362698
Received: April 26, 2019
Peer-review started: April 26, 2019
First decision: May 24, 2019
Revised: June 7, 2019
Accepted: July 19, 2019
Article in press: May 24, 2019
Published online: September 21, 2019
Abstract
BACKGROUND

Highly upregulated in liver cancer (HULC) is a long non-coding RNA (lncRNA) which has recently been identified as a key regulator in hepatocellular carcinoma (HCC) progression. However, its role in the secretion of exosomes from HCC cells remains unknown.

AIM

To explore the mechanism by which HULC promotes the secretion of exosomes from HCC cells.

METHODS

Serum and liver tissue samples were collected from 30 patients with HCC who had not received chemotherapy, radiotherapy, or immunotherapy before surgery. HULC expression in serum exosomes and liver cancer tissues of patients was measured, and compared with the data obtained from healthy controls and tumor adjacent tissues. The effect of HULC upregulation in HCC cell lines and the relationship between HULC and other RNAs were studied using qPCR and dual-luciferase reporter assays. Nanoparticle tracking analysis was performed to detect the quantity of exosomes.

RESULTS

HULC expression in serum exosomes of patients with HCC was higher than that in serum exosomes of healthy controls, and HULC levels were higher in liver cancer tissues than in tumor adjacent tissues. The expression of HULC in serum exosomes and liver cancer tissues correlated with the tumor-node-metastasis (TNM) classification, and HULC expression in tissues correlated with that in serum exosomes. Upregulation of HULC promoted HCC cell growth and invasion and repressed apoptosis. Notably, it also facilitated the secretion of exosomes from HCC cells. Moreover, qPCR assays showed that HULC repressed microRNA-372-3p (miR-372-3p) expression. We also identified Rab11a as a downstream target of miR-372-3p. Dual-luciferase reporter assays suggested that miR-372-3p could directly bind both HULC and Rab11a.

CONCLUSION

Our findings illustrate the importance of the HULC/miR-372-3p/Rab11a axis in HCC and provide new insights into the molecular mechanism regulating the secretion of exosomes from HCC cells.

Keywords: Long non-coding RNA, Exosomes, Hepatocellular carcinoma, miR-372-3p, Rab11a

Core tip: We found that (1) HULC expression was higher in serum exosomes of patients with HCC than in those of healthy controls, and higher in liver cancer tissues than in tumor adjacent tissues; (2) HULC expression in serum exosomes and liver cancer tissues were correlated with the TNM classification, and HULC expression in tissues was correlated with that in serum exosomes; (3) Increased HULC expression was associated with increased proliferation and invasion and reduced apoptosis of HCC cells; and (4) HULC repressed miR-372-3p expression, and miR-372-3p could directly bind both HULC and Rab11a. Furthermore, the HULC/ miR-372-3p /Rab11a axis promoted the secretion of exosomes from HCC cells.