Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 14, 2021; 27(6): 487-500
Published online Feb 14, 2021. doi: 10.3748/wjg.v27.i6.487
Circular RNA circVAPA promotes chemotherapy drug resistance in gastric cancer progression by regulating miR-125b-5p/STAT3 axis
Peng Deng, Ming Sun, Wen-Yan Zhao, Bin Hou, Kai Li, Tao Zhang, Feng Gu
Peng Deng, Bin Hou, Kai Li, Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
Ming Sun, Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
Wen-Yan Zhao, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
Tao Zhang, Department of Stem Cells and Regenerative Medicine, China Medical University, Shenyang 110122, Liaoning Province, China
Feng Gu, Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
Author contributions: Deng P and Sun M performed the majority of experiments and analyzed the data; Zhao WY performed the molecular investigations; Hou B and Gu F designed and coordinated the research; Li K and Zhang T wrote the paper.
Supported by Natural Science Foundation of Liaoning Province, No. 2019-MS-385.
Institutional review board statement: This study was reviewed and approved by the First Affiliated Hospital of China Medical University.
Institutional animal care and use committee statement: The animal study was reviewed and approved by the First Affiliated Hospital of China Medical University.
Conflict-of-interest statement: The authors declare no conflict of interest related to this manuscript.
Data sharing statement: No additional data are available.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Feng Gu, PhD, Chief Physician, Department of Ophthalmology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang 110001, Liaoning Province, China. fenggu78186069@163.com
Received: December 6, 2020
Peer-review started: December 6, 2020
First decision: December 17, 2020
Revised: December 21, 2020
Accepted: January 7, 2021
Article in press: January 7, 2021
Published online: February 14, 2021
Abstract
BACKGROUND

Gastric cancer (GC) is a prevalent malignancy, leading to a high incidence of cancer-associated death. Cisplatin (DDP)-based chemotherapy is the principal therapy for clinical GC treatment, but DDP resistance is a severe clinical challenge and the mechanism remains poorly understood. Circular RNAs (circRNAs) have been identified to play crucial roles in modulating the chemoresistance of gastric cancer cells.

AIM

To explore the effect of circVAPA on chemotherapy resistance during GC progression.

METHODS

The effect of circVAPA on GC progression and chemotherapy resistance was analyzed by MTT assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry analysis in GC cells and DDP resistant GC cell lines, and tumorigenicity analysis in nude mice in vivo. The mechanism was investigated by luciferase reporter assay, quantitative real-time PCR, and Western blot analysis.

RESULTS

CircVAPA expression was up-regulated in clinical GC tissues compared with normal samples. CircVAPA depletion inhibited proliferation, migration, and invasion and increased apoptosis of GC cells. The expression of circVAPA, STAT3, and STAT3 downstream genes was elevated in DDP resistant SGC7901/DDP cell lines. CircVAPA knockdown attenuated the DDP resistance of GC cells. Mechanically, circVAPA was able to sponge miR-125b-5p, and miR-125b-5p could target STAT3 in the GC cells. MiR-125b-5p inhibitor reversed circVAPA depletion-enhanced inhibitory effect of DDP on GC cells, and STAT3 knockdown blocked circVAPA overexpression-induced proliferation of DDP-treated SGC7901/DDP cells. The depletion of STAT3 and miR-125b-5p inhibitor reversed circVAPA depletion-induced GC cell apoptosis. Functionally, circVAPA contributed to the tumor growth of SGC7901/DDP cells in vivo.

CONCLUSION

CircVAPA promotes chemotherapy resistance and malignant progression in GC by miR-125b-5p/STAT3 signaling. Our findings present novel insights into the mechanism by which circVAPA regulates chemotherapy resistance of GC cells. CircVAPA and miR-125b-5p may be considered as the potential targets for GC therapy.

Keywords: Gastric cancer, Progression, Chemoresistance, CircVAPA, miR-125b-5p, STAT3

Core Tip: We concluded that circVAPA contributed to chemotherapy resistance and malignant progression in gastric cancer (GC) by miR-125b-5p/STAT3 signaling. Our findings present novel insights into the mechanism that circVAPA regulates chemotherapy resistance of GC cells. CircVAPA and miR-125b-5p may be considered as potential targets for GC therapy.