Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2023; 15(5): 787-809
Published online May 15, 2023. doi: 10.4251/wjgo.v15.i5.787
Circ_0003356 suppresses gastric cancer growth through targeting the miR-668-3p/SOCS3 axis
Wei-Dong Li, Hai-Tao Wang, Yue-Ming Huang, Bo-Hao Cheng, Li-Jun Xiang, Xin-Hao Zhou, Qing-Yan Deng, Zhi-Gang Guo, Zhi-Feng Yang, Zhi-Fen Guan, Yao Wang
Wei-Dong Li, Hai-Tao Wang, Yue-Ming Huang, Bo-Hao Cheng, Li-Jun Xiang, Xin-Hao Zhou, Qing-Yan Deng, Zhi-Gang Guo, Zhi-Feng Yang, Zhi-Fen Guan, Yao Wang, Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
Author contributions: Li WD, Wang HT, and Wang Y designed the study; Huang YM, Cheng BH, Xiang LJ, and Zhou XH collected the data; Deng QY, Guo ZG, Yang ZF, Guan ZF, and Wang Y analyzed the data; Li WD and Wang HT wrote the manuscript; and all authors approved the final manuscript.
Supported by Zhongshan Social Public Welfare and Basic Research Project, No. 200421093453685.
Institutional review board statement: The Ethics Committee of Zhongshan City People’s Hospital gave the approval (K2017-182).
Institutional animal care and use committee statement: All experiments were approved by the Animal Care and Use Committee of Zhongshan City People’s Hospital (K2017-182).
Informed consent statement: All participants have also agreed to this investigation by offering their written consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All the data used to support the findings of this study are included within the article.
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:
Corresponding author: Yao Wang, MD, Professor, Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Zhongshan 528403, Guangdong Province, China.
Received: November 30, 2022
Peer-review started: November 30, 2022
First decision: December 25, 2022
Revised: January 6, 2023
Accepted: April 7, 2023
Article in press: April 7, 2023
Published online: May 15, 2023

Circular RNAs (circRNAs) have attracted extensive attention as therapeutic targets in gastric cancer (GC). Circ_0003356 is known to be downregulated in GC tissues, but its cellular function and mechanisms remain undefined.


To investigate the role of circ_0003356 in GC at the molecular and cellular level.


Circ_0003356, miR-668-3p, and SOCS3 expression were assessed via quantitative real time-polymerase chain reaction (qRT-PCR). Wound healing, EdU, CCK-8, flow cytometry and transwell assays were used to analyze the migration, proliferation, viability, apoptosis and invasion of GC cells. The subcellular localization of circ_0003356 was monitored using fluorescence in situ hybridization. The interaction of circ_0003356 with miR-668-3p was confirmed using RIP-qRT-PCR, RNA pull-down, and dual luciferase reporter assays. We observed protein levels of genes via western blot. We injected AGS cells into the upper back of mice and performed immunohistochemistry staining for examining E-cadherin, N-cadherin, Ki67, and SOCS3 expressions. TUNEL staining was performed for the assessment of apoptosis in mouse tumor tissues.


Circ_0003356 and SOCS3 expression was downregulated in GC cells, whilst miR-668-3p was upregulated. Exogenous circ_0003356 expression and miR-668-3p silencing suppressed the migration, viability, proliferation, epithelial to mesenchy-mal transition (EMT) and invasion of GC cells and enhanced apoptosis. Circ_0003356 overexpression impaired tumor growth in xenograft mice. Targeting of miR-668-3p by circ_0003356 was confirmed through binding assays and SOCS3 was identified as a downstream target of miR-668-3p. The impacts of circ_0003356 on cell proliferation, apoptosis, migration, invasion and EMT were reversed by miR-668-3p up-regulation or SOCS3 down-regulation in GC cells.


Circ_0003356 impaired GC development through its interaction with the miR-668-3p/SOCS3 axis.

Keywords: Epithelial-mesenchymal transition, Circ_0003356, Gastric cancer, Invasion, Proliferation, Migration

Core Tip: We observed the low level of circ_0003356 expression in gastric cancer (GC) tissues and cells. Circ_0003356 expression was positively related to GC patient prognosis. Exogenous circ_0003356 overexpression and/or miR-668-3p suppression enhanced apoptosis in GC cells and suppressed GC cell proliferation, migration, invasion, and epithelial to mesenchy-mal transition. The overexpression of circ_0003356 also prevented tumor growth in mice. At the mechansistic level, circ_0003356 was found to interact with the miR-668-3p/SOCS3 axis to impair GC development. Together, we reveal new and important molecular details highlighting circ_0003356 as a novel cancer target.