Activation of interleukin-33/suppression of tumorigenicity 2 signaling contributes to gallbladder carcinoma-induced chronic pain

doi:10.4251/wjgo.v18.i3.115905

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World Journal of Gastrointestinal Oncology

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Oncol. Mar 15, 2026; 18(3): 115905
Published online Mar 15, 2026. doi: 10.4251/wjgo.v18.i3.115905

Activation of interleukin-33/suppression of tumorigenicity 2 signaling contributes to gallbladder carcinoma-induced chronic pain

Xian-Xiu Ge, Xin-Ming Dong, Yang Yang, Wen Zhang, Wei Zhou, Xue-Ting Deng

Xian-Xiu Ge, Xin-Ming Dong, Yang Yang, Xue-Ting Deng, Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China

Wen Zhang, Emergency Medicine Center, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi 210011, Jiangsu Province, China

Wei Zhou, Department of Child Health Care, Children’s Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China

Co-first authors: Xian-Xiu Ge and Xin-Ming Dong.

Co-corresponding authors: Wei Zhou and Xue-Ting Deng.

Author contributions: Ge XX and Dong XM made equal contributions as co-first authors; Deng XT and Zhou W designed the experiments with the help of Ge XX, analyzed the results, and drafted the manuscript, contributed equally as co-corresponding authors; Zhou W, Dong XM, Ge XX, Yang Y, Deng XT, and Zhang W performed the experiments; Deng XT secured funding for the project. All the authors have read and approved the final manuscript.

Supported by National Natural Science Foundation of China, No. 82171222.

Institutional review board statement: This study was approved by the Review Board of the Second Affiliated Hospital of Nanjing Medical University, No. 2018-KY-32-01.

Institutional animal care and use committee statement: All the animal experimental procedures were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University, No. IACUC-2106005.

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 of this study are available from the corresponding author or any co-author on request.

Corresponding author: Xue-Ting Deng, Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan, Nanjing 210011, Jiangsu Province, China. xtdeng@njmu.edu.cn

Received: October 29, 2025
Revised: December 9, 2025
Accepted: January 16, 2026
Published online: March 15, 2026
Processing time: 134 Days and 22.3 Hours

Abstract

BACKGROUND

Patients with gallbladder carcinoma (GBC) often report abdominal pain, which is particularly severe, difficult to treat, and insufficiently relieved. Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) signaling plays a role in cancer and pain, but its role in GBC-induced chronic pain is still unknown.

AIM

To investigate the potential effects of IL-33/ST2 signaling on GBC-induced cancer pain.

METHODS

To establish a GBC-induced chronic pain model, the GBC cell line GBC-SD was implanted into the gallbladder of nude mice. Pain-related behavior was determined by evaluating withdrawal behavior in response to mechanical stimuation. Serum samples from patients were analyzed via enzyme-linked immunolsorbent assay. Spinal cord samples from the rodents were subjected to enzyme-linked immunosorbent assay, western blotting and quantitative real-time polymerase chain reaction.

RESULTS

Nude mice with GBC-induced chronic pain presented significant spontaneous visceral pain-related behavior and abdominal hypersensitivity to mechanical stimuli. We demonstrated a significant increase in IL-33 levels in patient serum and in the spinal cords of GBC-induced chronic pain model mice. IL-33/ST2 signaling activation in the spinal cord may promote GBC-induced chronic pain. Remarkable activation of astrocytes and microglia as well as increased levels of proinflammatory cytokines was observed in the spinal cords of the mice. A significant decrease in the activation of astrocytes and microglia and the levels proinflammatory cytokines was observed following the blockade of IL-33/ST2 signaling.

CONCLUSION

Blockade of spinal IL-33/ST2 signaling results in a significant reduction in GBC-induced pain-related behaviors. This study suggested that targeting IL-33/ST2 signaling may relieve chronic cancer pain due to GBC.

Keywords: Interleukin-33; Gallbladder carcinoma; Chronic cancer-related pain; Spinal cord; Proinflammatory cytokines

Core Tip: This study revealed the role of spinal interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) signaling in the pathogenesis of gallbladder carcinoma (GBC)-induced chronic pain. IL-33/ST2 activation is critical for the genesis and maintenance of GBC-induced chronic pain. Blockade of IL-33/ST2 signaling in the spinal cord results in a significant reduction in pain-related behaviors as well as the proinflammatory cytokine levels in rodents with GBC-induced chronic pain. This study suggested that targeting IL-33/ST2 signaling may relieve chronic cancer pain due to gallbladder carcinoma.