Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 14, 2023; 29(46): 6060-6075
Published online Dec 14, 2023. doi: 10.3748/wjg.v29.i46.6060
Exosome-mediated transfer of circRNA563 promoting hepatocellular carcinoma by targeting the microRNA148a-3p/metal-regulatory transcription factor-1 pathway
Zhuo-Zhen Lyu, Meng Li, Ming-Yu Yang, Mei-Hong Han, Zhen Yang
Zhuo-Zhen Lyu, Meng Li, Ming-Yu Yang, Mei-Hong Han, Zhen Yang, Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
Author contributions: Yang Z designed and coordinated the study, and wrote the manuscript; Lyu ZZ, Li M, Yang MY, and Han MH performed the experiments; Lyu ZZ, Li M, Han MH, and Yang Z acquired and analyzed the data; Lyu ZZ, Han MH, and Yang Z interpreted the data; and all authors approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 81972606 and 82271774.
Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Medical Ethics Committee of Shandong Provincial Hospital (protocol code NSFC: NO.2019-012; date of approval: 02/19/2019).
Institutional animal care and use committee statement: The animal study was approved by the Animal Ethics Committee of Shandong Provincial Hospital (protocol code NSFC: NO.2019-021; approval date: 02/19/2019).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zhen Yang, MD, PhD, Doctor, Professor, Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwu Road, Jinan 250021, Shandong Province, China. yangzhen@sdfmu.edu.cn
Received: September 29, 2023
Peer-review started: September 29, 2023
First decision: October 16, 2023
Revised: October 24, 2023
Accepted: November 17, 2023
Article in press: November 17, 2023
Published online: December 14, 2023
Processing time: 74 Days and 18.5 Hours
Abstract
BACKGROUND

Mesenchymal stem cells (MSCs) exert anti-oncogenic effects via exosomes containing non-coding RNA (ncRNA), which play important roles in tumor biology. Our preliminary study identified the interaction of the ncRNA hsa_circ_0000563 (circ563) and the circ563-associated miR-148a-3p in exosomes, as miR-148a-3p and its target metal-regulatory transcription factor-1 (MTF-1) are implicated in hepatocellular carcinoma (HCC) progression.

AIM

To identify the clinical significance, functional implications, and mechanisms of circ563 in HCC.

METHODS

The expression levels of miR-148a-3p and MTF-1 in exosomes derived from MSC and HCC cells were compared, and their effects on HCC cells were assessed. Using a dual-luciferase reporter assay, miR-148a-3p was identified as an associated microRNA of circ563, whose role in HCC regulation was assessed in vitro and in vivo.

RESULTS

The silencing of circ563 blocked the HCC cell proliferation and invasion and induced apoptosis. Co-culturing of HCC cells with MSC-derived exosomes following circ563 overexpression promoted cell proliferation and metastasis and elicited changes in miR-148a-3p and MTF-1 expression. The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or MTF-1 depletion. Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth by upregulating the expression of MTF-1. In HCC tissues, circ563 expression was negatively correlated with miR-148a-3p expression but positively correlated with MTF-1 levels.

CONCLUSION

MSCs may exhibit anti-HCC activity through the exosomal circ563/miR-148a-3p/MTF-1 pathway, while exosomes can transmit circ563 to promote oncogenic behavior by competitively binding to miR-148a-3p to activate MTF-1.

Keywords: Exosome; Cell communication; Noncoding RNA; Metal-regulatory transcription factor-1; Mesenchymal stem cells

Core Tip: We identified the functional implications and mechanisms of exosomal hsa_circ_0000563 (circ563) in hepatocellular carcinoma (HCC). Mesenchymal stem cells suppressed HCC proliferation and invasion via their exosomes. The circ563 interacts with miR-148a-3p, a molecule involved in HCC progression, and both are identified at different levels in exosomes. The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or depletion of metal-regulatory transcription factor-1 (MTF-1). Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth via MTF-1 upregulation. Our findings provide new insights into circ563/miR-148a-3p/MTF-1 signaling as a potential therapeutic target for HCC.