Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2023; 15(8): 1384-1399
Published online Aug 15, 2023. doi: 10.4251/wjgo.v15.i8.1384
Antitumor activity of miR-188-3p in gastric cancer is achieved by targeting CBL expression and inactivating the AKT/mTOR signaling
Jian-Jiao Lin, Bao-Hua Luo, Tao Su, Qiong Yang, Qin-Fei Zhang, Wei-Yu Dai, Yan Liu, Li Xiang
Jian-Jiao Lin, Tao Su, Qin-Fei Zhang, Yan Liu, Li Xiang, Department of Gastroenterology, The Second Affiliated Hospital of Chinese University of Hong Kong (Shenzhen Longgang District People's Hospital), Shenzhen 518172, Guangdong Province, China
Bao-Hua Luo, Department of Urology, Hospital of Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China
Qiong Yang, Department of Gastroenterology, The Second Affiliated Hospital of the University of South China, Hengyang 421001, Hunan Province, China
Wei-Yu Dai, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
Author contributions: All authors contributed significantly to this work, whether in the conception, study design, execution, acquisition of data, analysis, and interpretation or in all these areas; Specifically, Lin JJ, Luo BH, and Xiang L designed and conceived the study. Su T, Yang Q performed in vitro experiments, Dai WY conducted in vitro experiments, and Zhang QF helped with data analysis; Liu Y and Lin JJ wrote the manuscript; All authors read and approved the final version of this manuscript.
Supported by the National Natural Science Funds of China, No. 81974448; Guangdong Medical Research Foundation, No. B2019126; and Shenzhen Science and Technology Innovation Commission, No. JCYJ20210324135005013.
Institutional review board statement: This study protocols were by the Institutional Ethical Standards Committee of Nanfang Hospital (#NFEC-2019-010), Southern Medical University (Guangzhou, China). All experiments were performed in accordance with the relevant guidelines and regulations.
Informed consent statement: Informed consent statement was waived due to the retrospective nature of the study.
Institutional animal care and use committee statement: All animal procedures were reviewed and approved by the Experimental Animal Ethics Committee of The Second Affiliated Hospital of the Chinese University of Hong Kong, Shenzhen (Longgang District People's Hospital).
Conflict-of-interest statement: There is no conflict of interest in this study.
Data sharing statement: The datasets generated and 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: Li Xiang, PhD, Doctor, Department of Gastroenterology, The Second Affiliated Hospital of Chinese University of Hong Kong (Shenzhen Longgang District People's Hospital), No. 53 Aixin Road, Shenzhen 518172, Guangdong Province, China.shellyxiangli@163.com
Received: March 30, 2023
Peer-review started: March 30, 2023
First decision: April 25, 2023
Revised: May 29, 2023
Accepted: July 7, 2023
Article in press: July 7, 2023
Published online: August 15, 2023
Abstract
BACKGROUND

Altered miR-188-3p expression has been observed in various human cancers.

AIM

To investigate the miR-188-3p expression, its roles, and underlying molecular events in gastric cancer.

METHODS

Fifty gastric cancer and paired normal tissues were collected to analyze miR-188-3p and CBL expression. Normal and gastric cancer cells were used to manipulate miR-188-3p and CBL expression through different assays. The relationship between miR-188-3p and CBL was predicted bioinformatically and confirmed using a luciferase gene reporter assay. A Kaplan-Meier analysis was used to associate miR-188-3p or CBL expression with patient survival. A nude mouse tumor cell xenograft assay was used to confirm the in vitro data.

RESULTS

MiR-188-3p was found to be lower in the plasma of gastric cancer patients, tissues, and cell lines compared to their healthy counterparts. It was associated with overall survival of gastric cancer patients (P < 0.001), tumor differentiation (P < 0.001), lymph node metastasis (P = 0.033), tumor node metastasis stage (I/II vs III/IV, P = 0.024), and American Joint Committee on Cancer stage (I/II vs III/IV, P = 0.03). Transfection with miR-188-3p mimics reduced tumor cell growth and invasion while inducing apoptosis and autophagy. CBL was identified as a direct target of miR-188-3p, with its expression antagonizing the effects of miR-188-3p on gastric cancer (GC) cell proliferation by inducing tumor cell apoptosis and autophagy through the inactivation of the Akt/mTOR signaling pathway. The in vivo data confirmed antitumor activity via CBL downregulation in gastric cancer.

CONCLUSION

The current data provides ex vivo, in vitro, and in vivo evidence that miR-188-3p acts as a tumor suppressor gene or possesses antitumor activity in GC.

Keywords: Gastric cancer, miR-188-3p, Tumor cell proliferation, Autophagy, AKT/mTOR signaling pathway, CBL expression

Core Tip: Our study provided evidence for the antitumor activity of miR-188-3p in gastric cancer. We investigated the underlying molecular mechanisms by demonstrating that miR-188-3p inhibits gastric cancer progression and malignant behavior by suppressing Akt/mTOR signaling pathway activity and targeting CBL expression.