Downregulation of uncoupling protein 1 by hypermethylation in gastric cancer activates Rap1 signaling

doi:10.4251/wjgo.v17.i9.108760

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World Journal of Gastrointestinal Oncology

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastrointest Oncol. Sep 15, 2025; 17(9): 108760
Published online Sep 15, 2025. doi: 10.4251/wjgo.v17.i9.108760

Downregulation of uncoupling protein 1 by hypermethylation in gastric cancer activates Rap1 signaling

Yi-Jia Chen, Cheng Peng, Li-Wei Wang, Jia-Xin Chai, Jian-Dong Wang, Qi-Bin He

Yi-Jia Chen, Cheng Peng, Li-Wei Wang, Qi-Bin He, Department of Gastroenterology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China

Jia-Xin Chai, Jian-Dong Wang, Department of Pathology, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing 210002, Jiangsu Province, China

Co-first authors: Yi-Jia Chen and Cheng Peng.

Co-corresponding authors: Jian-Dong Wang and Qi-Bin He.

Author contributions: Chen YJ and Peng C contributed equally to this work as co-first authors. This designation accurately reflects the collaborative distribution of responsibilities and effort required for the study and manuscript, enhances post-submission management to improve paper quality, best represents the diverse expertise within our multidisciplinary team for comprehensive topic examination, acknowledges the researchers' equal substantive contributions throughout the research process, and embodies our team's collaborative spirit, equal contributions, and diversity. Wang JD and He QB share corresponding authorship for this work. This designation recognizes their joint leadership in research design and academic supervision, ensuring rigor in methodology and data analysis; shared responsibility for manuscript drafting, critical revision, and ethical compliance; integration of complementary expertise across disciplines for multidimensional scholarly guidance; coordinated management of journal communications, reader inquiries, and knowledge dissemination; and embodiment of collaborative governance to uphold research integrity and academic impact; Wang LW and Chai JX collected clinical samples and performed IHC; all authors reviewed the manuscript.

Supported by the Nanjing Health Science and Technology Development Fund, No. YKK24223.

Institutional review board statement: This study was approved by the Medical Ethics Committee of The Affiliated Jiangning Hospital of Nanjing Medical University, China. Informed consent was waived due to the retrospective nature of this study.

Institutional animal care and use committee statement: All procedures involving animals were conducted in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and were approved by the Affiliated Jiangning Hospital of Nanjing Medical University, China. This study was designed to minimize animal suffering and ensure their humane treatment in compliance with all applicable federal, state, and institutional regulations. Animals were housed in accordance with the guidelines of the Affiliated Jiangning Hospital of Nanjing Medical University Animal Care Facility, and all efforts were made to reduce the number of animals used and to refine the experimental procedures.

Conflict-of-interest statement: The authors declare that they have no competing interests.

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 that support this work are available from the corresponding author upon reasonable request.

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: Qi-Bin He, Director, Professor, Department of Gastroenterology, The Affiliated Jiangning Hospital of Nanjing Medical University, No. 169 Hushan Road, Jiangning District, Nanjing 211100, Jiangsu Province, China. 13770936117@163.com

Received: April 24, 2025
Revised: June 13, 2025
Accepted: July 22, 2025
Published online: September 15, 2025
Processing time: 145 Days and 9.6 Hours

Abstract

BACKGROUND

Uncoupling protein 1 (UCP1) plays a pivotal role in modulating energy expenditure and maintaining metabolic homeostasis within brown and beige adipocytes. It has also been implicated in tumorigenesis.

AIM

To investigate the expression and function of UCP1 in gastric cancer (GC).

METHODS

UCP1 protein expression in 211 GC tissues was examined using immunohistochemistry. Bisulfite sequencing PCR (BSP) was used to detect the methylation status of the UCP1 promoter in GC cell lines and tissues. The relationship between UCP1 expression and clinicopathological parameters was analyzed. CCK8, scratch, transwell, and flow cytometry assays were carried out to analyze the proliferation, migration, invasion, and apoptosis of GC cell lines after knockdown or overexpression of UCP1 in vitro. A nude mouse tumor xenograft model was used to investigate the function of UCP1 in vivo. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes analysis, and Rap1 pull-down assays were performed to identify the pathway associated with UCP1.

RESULTS

Loss of UCP1 was significantly associated with gender, poor differentiation, and advanced TNM stage of GC. Hypermethylation of UCP1 was confirmed in GC cells and tumor tissues by BSP. Overexpression of UCP1 suppressed GC cell proliferation, migration, and invasion, and it promoted apoptosis in vitro. UCP1 overexpression also suppressed GC tumor growth in vivo. Moreover, overexpression of UCP1 in GC cells resulted in a significant decrease in active Rap1 protein levels, whereas downregulation of UCP1 markedly enhanced Rap1 activity.

CONCLUSION

UCP1 downregulation in GC through promoter hypermethylation is related to the progression of GC, indicating that UCP1 plays a role as a tumor suppressor in GC. It regulates Rap1 signaling and may be a potential therapeutic target in GC.

Keywords: Uncoupling protein 1; Gastric cancer; Hypermethylation; Rap1 signaling

Core Tip: Uncoupling protein 1 (UCP1) plays a significant role in regulating energy expenditure and metabolic homeostasis in brown and beige adipocytes. Hypermethylation of UCP1 was confirmed in gastric cancer (GC) cells and tumor tissues. Overexpression of UCP1 suppressed GC cell proliferation, migration, and invasion, and it promoted apoptosis in vitro. Overexpression of UCP1 also suppressed GC tumor growth in vivo. The level of active Rap1 protein in GC cells was significantly decreased with UCP1 overexpression and significantly increased after UCP1 knockdown. UCP1 plays a role as a tumor suppressor in GC; it regulates Rap1 signaling and may be a potential therapeutic target in GC.