Li DG, Jiang JP, Chen FY, Wu W, Fu J, Wang GH, Li YB. Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors. World J Gastrointest Oncol 2024; 16(8): 3585-3599 [PMID: 39171181 DOI: 10.4251/wjgo.v16.i8.3585]
Corresponding Author of This Article
Yu-Bo Li, MM, Associate Chief Physician, Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No. 89-9 Dongge Road, Nanning 530023, Guangxi Zhuang Autonomous Region, China. gzyzyyfygc@126.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
World J Gastrointest Oncol. Aug 15, 2024; 16(8): 3585-3599 Published online Aug 15, 2024. doi: 10.4251/wjgo.v16.i8.3585
Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors
De-Gang Li, Jia-Peng Jiang, Fan-Ye Chen, Wei Wu, Jun Fu, Gong-He Wang, Yu-Bo Li
De-Gang Li, Jia-Peng Jiang, Fan-Ye Chen, Wei Wu, Jun Fu, Gong-He Wang, Yu-Bo Li, Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
Author contributions: Li DG and Li YB designed the study; Jiang JP, Chen FY and Wu W collected the data; Fu J, Wang GH and Li YB analyzed the data; Li DG wrote the manuscript. All authors reviewed and approved the final manuscript.
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Ethics Committee of Beijing Viewsolid Biotechnology Co. LTD (VS2126A00170).
Conflict-of-interest statement: All authors have nothing to disclose.
Data sharing statement: The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary materials.
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: Yu-Bo Li, MM, Associate Chief Physician, Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No. 89-9 Dongge Road, Nanning 530023, Guangxi Zhuang Autonomous Region, China. gzyzyyfygc@126.com
Received: January 5, 2024 Revised: June 6, 2024 Accepted: June 25, 2024 Published online: August 15, 2024 Processing time: 215 Days and 21.7 Hours
Abstract
BACKGROUND
Gastrointestinal stromal tumors (GISTs) are typical gastrointestinal tract neoplasms. Imatinib is the first-line therapy for GIST patients. Drug resistance limits the long-term effectiveness of imatinib. The regulatory effect of insulin-like growth factor 2 (IGF2) has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.
AIM
To further investigate the mechanism of IGF2 specific to GISTs.
METHODS
IGF2 was screened and analyzed using Gene Expression Omnibus (GEO: GSE225819) data. After IGF2 knockdown or overexpression by transfection, the phenotypes (proliferation, migration, invasion, apoptosis) of GIST cells were characterized by cell counting kit 8, Transwell, and flow cytometry assays. We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition (EMT)-associated proteins. We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.
RESULTS
Data from the GEO indicated that IGF2 expression is high in GISTs, associated with liver metastasis, and closely related to drug resistance. GIST cells with high expression of IGF2 had increased proliferation and migration, invasiveness and EMT. Knockdown of IGF2 significantly inhibited those activities. In addition, OE-IGF2 promoted GIST metastasis in vivo in nude mice. IGF2 activated IGF1R signaling in GIST cells, and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis. GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance. Moreover, 2-deoxy-D-glucose (a glycolysis inhibitor) treatment reversed IGF2 overexpression-mediated imatinib resistance in GISTs.
CONCLUSION
IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.
Core Tip: Our study found that insulin-like growth factor 2 (IGF2) regulated metastasis and imatinib resistance in gastrointestinal stromal tumors (GISTs). IGF2 interacted with IGF1R to regulate glycolysis. Our results confirm that IGF2 targeting of IGF1R signaling inhibited metastasis and improved imatinib chemosensitivity by driving glycolysis in GISTs and indicated that IGF2 might be used to reverse imatinib resistance in GIST patients.
