Basic Study
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World J Gastrointest Oncol. Mar 15, 2025; 17(3): 97673
Published online Mar 15, 2025. doi: 10.4251/wjgo.v17.i3.97673
Transmembrane protein 176B promotes epithelial-mesenchymal transition in colorectal cancer through inflammasome inhibition
Wei Qian, Chong-Yi Xu, Wei Hong, Zhe-Ming Li, Dao-Gun Xu
Wei Qian, Chong-Yi Xu, Wei Hong, Dao-Gun Xu, Department of Proctology, Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Wenling 317500, Zhejiang Province, China
Zhe-Ming Li, College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
Author contributions: Qian W conceptualized the study, analyzed the data, developed the methodology, administered the project, and wrote the original draft; Xu CY curated the data, conducted formal analysis, and performed experiments; Hong W conducted formal analysis, performed experiments, and developed the methodology; Li ZM performed experiments, developed the methodology, and contributed to visualization; Xu DG conceptualized the study, acquired funding, administered the project, supervised the work, and reviewed and edited the manuscript. All the authors have read and approved the final manuscript.
Supported by Ministry of Education Industry-University Co-operation Collaborative Education Project, No. 202102242020.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Wenling Hospital of Traditional Chinese Medicine.
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Experimentation Ethics Committee of the Zhejiang Eyong Pharmaceutical Research and Development Center (Approval No.: ZJEY-20231130-01) and conducted according to the guidelines of the Institutional Animal Care and Use Committee.
Conflict-of-interest statement: The authors declare no competing interests relevant to the contents of this article.
Data sharing statement: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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: Dao-Gun Xu, BMed, Dean, Department of Proctology, Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, No. 21 Mingyuan Road, Taiping Street, Wenling 317500, Zhejiang Province, China. 13906569665@163.com
Received: June 5, 2024
Revised: October 30, 2024
Accepted: December 4, 2024
Published online: March 15, 2025
Processing time: 254 Days and 7 Hours
Abstract
BACKGROUND

Activation of the epithelial-mesenchymal transition (EMT), a pivotal process in tumor metastasis and evasion, as well as the NLRP3 inflammasome, both promote colorectal cancer (CRC) progression. Recent studies have shown that Transmembrane protein 176B (TMEM176B) regulates NLRP3 and promotes CRC malignant phenotypes.

AIM

To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.

METHODS

CRC in situ mouse and co-cultured cell models were established using CT26 cells, BALB/c mice, and primary cultured mouse natural killer (NK) cells. Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells. Fluorescence imaging, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, immunohistochemistry staining, flow cytometry, and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis, apoptosis, and EMT indicators.

RESULTS

Silencing TMEM176B in CRC mice significantly reduced tumor metastasis, proliferation, and EMT, while activating apoptosis, NLRP3 inflammasome, and NK cell activity. Furthermore, silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion, and promoted apoptosis. The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65, matrix metallopeptidase 9, and transforming growth factor-β.

CONCLUSION

This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.

Keywords: Transmembrane protein 176B; Epithelial-mesenchymal transition; Colorectal cancer; Pyrin domain containing 3 inflammasome; Natural killer cell

Core Tip: Silencing Transmembrane protein 176B (TMEM176B) inhibited tumor metastasis, proliferation, and epithelial-mesenchymal transition in colorectal cancer (CRC) in situ, in mice co-cultured with natural killer (NK) cells, while activating apoptosis, NLRP3 inflammasome, and NK cell function. The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65, matrix metallopeptidase 9, and transforming growth factor-β. This study highlights the critical role of TMEM176B/NLRP3 in CRC management, providing a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.