Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2024; 16(11): 4436-4455
Published online Nov 15, 2024. doi: 10.4251/wjgo.v16.i11.4436
BIRC3 induces the phosphoinositide 3-kinase-Akt pathway activation to promote trastuzumab resistance in human epidermal growth factor receptor 2-positive gastric cancer
Shu-Liang Li, Pei-Yao Wang, Yang-Pu Jia, Zhao-Xiong Zhang, Hao-Yu He, Peng-Yu Chen, Xin Liu, Bang Liu, Li Lu, Wei-Hua Fu
Shu-Liang Li, Pei-Yao Wang, Yang-Pu Jia, Zhao-Xiong Zhang, Hao-Yu He, Peng-Yu Chen, Xin Liu, Bang Liu, Li Lu, Wei-Hua Fu, Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
Shu-Liang Li, Department of Gastrointestinal Surgery, The Second People’s Hospital of Liaocheng, Liaocheng 252600, Shandong Province, China
Shu-Liang Li, Department of Gastrointestinal Surgery, The Second Hospital of Liaocheng, Affiliated to Shandong First Medical University, Liaocheng 252600, Shandong Province, China
Co-first authors: Shu-Liang Li and Pei-Yao Wang.
Author contributions: Li SL and Jia YP contributed to conceptualization, methodology, validation, data curation; Zhang ZX and Liu X contributed to formal analysis and investigation; Liu B and Lu L contributed to supervision, funding acquisition; He HY and Chen PY contributed to writing original draft preparation; Wang PY contributed to writing, review and editing; Fu WH contributed to funding acquisition, review and editing; All authors have read and approve the final manuscript.
Supported by the Tianjin Municipal Education Commission Scientific Research Project, No. 2018KJ055.
Institutional review board statement: The study was reviewed and approved by The Ethical Committee of Tianjin Medical University General Hospital, No. IRB2023-WZ-224.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Tianjin Medical University General Hospital, No. IRB2023-DW-138.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at tjmughgs_fwh@163.com. Participants gave informed oral consent for data sharing.
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: Wei-Hua Fu, MD, PhD, Professor, Surgeon, Teacher, Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, No. 154 Anshan Road, Tianjin 300052, China. tjmughgs_fwh@163.com
Received: April 23, 2024
Revised: August 13, 2024
Accepted: September 10, 2024
Published online: November 15, 2024
Processing time: 185 Days and 9.1 Hours
Abstract
BACKGROUND

Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer. However, the emergence of resistance to trastuzumab poses significant challenges.

AIM

To identify the key genes associated with trastuzumab resistance. These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.

METHODS

High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation. Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance. We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3, followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.

RESULTS

In patients with HER2-positive gastric cancer, there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage, tumor node metastasis stage, as well as poor overall survival and progression-free survival. BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines, where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt (PI3K-AKT) pathway in HER2-positive gastric cancer cells, both in vivo and in vitro.

CONCLUSION

This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer. Thus, the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation, stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis, ultimately leading to trastuzumab resistance.

Keywords: Gastric cancer; Human epidermal growth factor receptor 2; Trastuzumab; Drug-resistance; BIRC3

Core Tip: Our study discovered that the overexpression of BIRC3 leads to the stimulation of phosphoinositide 3-kinase-Akt phosphorylation and activation. Consequently, this enhances the proliferation of human epidermal growth factor receptor 2-positive tumor cells and inhibits apoptosis, resulting in resistance to trastuzumab.