Nian H, Bai Y, Wang HY, Yu H, Zhang ZL, Shi RH, Zhang S, Wu YB, Zhou DH, Du QC. Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors. World J Gastrointest Oncol 2025; 17(11): 109923 [DOI: 10.4251/wjgo.v17.i11.109923]
Corresponding Author of This Article
Qian-Cheng Du, MD, Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, No. 366 Longchuan North Road, Xuhui District, Shanghai 200031, China. duqc1991106@sina.com
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Gastroenterology & Hepatology
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Minireviews
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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/
Nov 15, 2025 (publication date) through Nov 13, 2025
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World Journal of Gastrointestinal Oncology
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1948-5204
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Nian H, Bai Y, Wang HY, Yu H, Zhang ZL, Shi RH, Zhang S, Wu YB, Zhou DH, Du QC. Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors. World J Gastrointest Oncol 2025; 17(11): 109923 [DOI: 10.4251/wjgo.v17.i11.109923]
World J Gastrointest Oncol. Nov 15, 2025; 17(11): 109923 Published online Nov 15, 2025. doi: 10.4251/wjgo.v17.i11.109923
Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors
Hui Nian, Yu Bai, Hong-Yang Wang, Hua Yu, Zhi-Long Zhang, Ru-Hong Shi, Shu Zhang, Yi-Bin Wu, De-Hua Zhou, Qian-Cheng Du
Hui Nian, Zhi-Long Zhang, Qian-Cheng Du, Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
Yu Bai, Yi-Bin Wu, Intensive Care Unit, Shanghai Xuhui Central Hospital, Shanghai 200031, China
Hong-Yang Wang, Department of Nursing, Shanghai Xuhui Central Hospital, Shanghai 200031, China
Hua Yu, Department of General Surgery, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, China
Ru-Hong Shi, De-Hua Zhou, Department of Gastrointestinal Surgery, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, China
Shu Zhang, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Co-first authors: Hui Nian and Yu Bai.
Co-corresponding authors: De-Hua Zhou and Qian-Cheng Du.
Author contributions: Nian H and Bai Y wrote and edited the manuscript as well as drew the figures and conducted a comprehensive literature search. They played an important and indispensable role in the pre-publication preparations, including literature retrieval, paper preparation and writing, and revision of the paper, and are co-first authors; Wang HY, Yu Hua, Zhang ZL, Shi RH, Zhang Shu and Wu YB made the figure and table of the manuscript. Zhou DH and Du QC conceptualized and designed the research. Both authors made critical and indispensable contributions to the completion of the project and are thus qualified as co-corresponding authors of this paper; all authors have read and approved the final manuscript.
Supported by Hongkou District Health Commission of Shanghai Municipality, No. “Hongwei”2303-10.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
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: Qian-Cheng Du, MD, Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, No. 366 Longchuan North Road, Xuhui District, Shanghai 200031, China. duqc1991106@sina.com
Received: May 27, 2025 Revised: June 14, 2025 Accepted: September 24, 2025 Published online: November 15, 2025 Processing time: 172 Days and 18 Hours
Abstract
Osteopontin (OPN), a key extracellular matrix protein, promotes gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. OPN enhances tumor proliferation and survival through mechanistic target of rapamycin and B-cell lymphoma 2 upregulation (e.g., via denticleless E3 ubiquitin protein ligase homolog in hepatocellular carcinoma) and drives metastasis via PI3K/AKT-mediated epithelial-mesenchymal transition and androgen receptor (AR) activation (e.g., via the OPN-RAN-AR axis in pancreatic cancer). Additionally, OPN induces chemoresistance by activating anti-apoptotic proteins (e.g., XIAP via CXCR3/PI3K/AKT in colorectal cancer) and remodels the tumor microenvironment through VEGF-dependent angiogenesis and cluster of differentiation 44-PI3K/AKT-mediated immune evasion. Its interaction with TLR4, WNT, and other pathways amplifies oncogenic effects. Therapies targeting the OPN-PI3K/AKT axis (e.g., PI3K inhibitors like LY294002) or combination treatments (e.g., with EGFR-TKIs) show promise for reversing drug resistance. Future research should focus on OPN isoform specificity, clinical translation, and interactions with autophagy and long non-coding RNAs to refine precision therapies. This review summarizes recent advances in understanding the molecular mechanisms, therapeutic targets, and clinical challenges of the OPN-PI3K/AKT axis in gastrointestinal tumors, providing a foundation for overcoming resistance and developing precision therapies.
Core Tip: Osteopontin (OPN) drives gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, promoting proliferation, metastasis, chemoresistance, and immune evasion. Key mechanisms involve upregulating anti-apoptotic proteins (e.g., B-cell lymphoma 2), inducing epithelial-mesenchymal transition via Snail/Twist, and remodeling the tumor microenvironment through VEGF-driven angiogenesis and cluster of differentiation 44-mediated immune suppression. Targeting this axis with PI3K/AKT inhibitors (e.g., Alpelisib) or OPN-neutralizing antibodies may reverse drug resistance and suppress metastasis. Challenges include pathway redundancy and the need for biomarker-guided precision strategies. Future research should focus on OPN isoform specificity, combination therapies (e.g., with immune checkpoint inhibitors), and multi-omics approaches to optimize outcomes in refractory cancers.
