Zhao ZX, Liu QL, Fan JX, Zhu S, Wang FS, Hu ZJ. Cadherin 6 drives epithelial-mesenchymal transition and oxaliplatin resistance in gastric cancer via transforming growth factor-β/Smad signaling axis. World J Gastrointest Oncol 2026; 18(6): 118121 [DOI: 10.4251/wjgo.v18.i6.118121]
Corresponding Author of This Article
Zong-Ju Hu, PhD, Department of General Surgery, Fuyang People’s Hospital, No. 501 Sanqing Road, Yingzhou District, Fuyang 236000, Anhui Province, China. hzj130123@126.com
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Gastroenterology & Hepatology
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research-article
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Zhao ZX, Liu QL, Fan JX, Zhu S, Wang FS, Hu ZJ. Cadherin 6 drives epithelial-mesenchymal transition and oxaliplatin resistance in gastric cancer via transforming growth factor-β/Smad signaling axis. World J Gastrointest Oncol 2026; 18(6): 118121 [DOI: 10.4251/wjgo.v18.i6.118121]
World J Gastrointest Oncol. Jun 15, 2026; 18(6): 118121 Published online Jun 15, 2026. doi: 10.4251/wjgo.v18.i6.118121
Cadherin 6 drives epithelial-mesenchymal transition and oxaliplatin resistance in gastric cancer via transforming growth factor-β/Smad signaling axis
Zong-Xian Zhao, Qin-Lingfei Liu, Jie-Xi Fan, Shu Zhu, Fu-Sheng Wang, Zong-Ju Hu
Zong-Xian Zhao, Qin-Lingfei Liu, Jie-Xi Fan, Shu Zhu, Zong-Ju Hu, Department of General Surgery, Fuyang People’s Hospital, Fuyang 236000, Anhui Province, China
Fu-Sheng Wang, Department of Anorectal Surgery, Fuyang People’s Hospital, Fuyang 236000, Anhui Province, China
Co-corresponding authors: Fu-Sheng Wang and Zong-Ju Hu.
Author contributions: Zhao ZX contributed to the experiments; Zhao ZX and Liu QL contributed to writing of the manuscript; Fan JX and Zhu S conceptualized and designed the research study; Hu ZJ assisted in the design of the study; Wang FS provided administrative, material support, and critical revisions; Wang FS and Hu ZJ contributed equally as co-corresponding authors. All authors read and approved the final version of the manuscript.
Supported by Anhui Provincial Health Commission, No. AHWJ2023Baa20164 and No. AHWJ2023BBa20054.
Institutional review board statement: The study was approved by the Ethics Committee of Fuyang People’s Hospital, No.[2022]81.
Institutional animal care and use committee statement: All animal procedures were approved by Institute of Health and Medical, Hefei Comprehensive National Science Center, No. IHM-AP-2025-075.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data generated or analyzed in this study are available from the corresponding author.
Corresponding author: Zong-Ju Hu, PhD, Department of General Surgery, Fuyang People’s Hospital, No. 501 Sanqing Road, Yingzhou District, Fuyang 236000, Anhui Province, China. hzj130123@126.com
Received: December 25, 2025 Revised: January 18, 2026 Accepted: February 25, 2026 Published online: June 15, 2026 Processing time: 167 Days and 18.5 Hours
Abstract
BACKGROUND
Gastric cancer (GC) is a globally prevalent, lethal malignancy with high recurrence rates and chemotherapy resistance, posing major clinical challenges. Cadherin 6 (CDH6) is involved in gastric oncogenesis, but its molecular mechanisms in GC remain unclear.
AIM
To investigate the specific biological functions of CDH6 in the transforming growth factor (TGF)-β pathway and oxaliplatin resistance of GC.
METHODS
We performed in vitro experiments using HGC-27/AGS cells with stable overexpression of CDH6, as well as in vivo xenograft experiments in BALB/c-nu mice. Bioinformatics analysis and clinical validation with GC samples were also conducted. Rescue experiments using a TGF-β inhibitor were performed to confirm pathway dependence.
RESULTS
CDH6 overexpression significantly enhanced migration, invasion, and proliferation of GC cells, and was correlated with poor patient prognosis. It increased half-maximal inhibitory concentrations of oxaliplatin and reduced the drug sensitivity of GC in vitro and in vivo. Mechanistically, CDH6 activated the TGF-β/Smad pathway (upregulating TβRI, Smad2, and phosphorylated Smad2) and promoted epithelial-mesenchymal transition (EMT), with downregulation of epithelial markers (E-cadherin and zonula occludens-1) and upregulation of mesenchymal markers (vimentin and α-smooth muscle actin). Rescue experiments showed that TGF-β inhibition reversed CDH6-induced phenotypes, including increased migration, invasion, proliferation, oxaliplatin resistance, and EMT.
CONCLUSION
CDH6 promotes progression and oxaliplatin resistance of GC by activating the TGF-β/Smad pathway and promoting EMT. This pathway could therefore be targeted as part of a novel strategy to improve therapeutic outcomes in GC.
Core Tip: Gastric cancer (GC) is among the most prevalent and lethal malignancies globally and the molecular mechanisms of cadherin 6 (CDH6) in GC remain unclear. We verified that CDH6 is a key regulator in GC progression and oxaliplatin resistance. Mechanistically, CDH6 exerts its oncogenic effects by activating the transforming growth factor-β pathway and promoting epithelial-mesenchymal transition. Targeting the CDH6/transforming growth factor-β/Smad axis may serve as a promising therapeutic strategy to overcome oxaliplatin resistance and improve clinical outcomes in GC patients.
