Up-regulation of protein C contributes to the progression of gastric cancer by modulating the MDM2/p53 axis

doi:10.4251/wjgo.123488

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World Journal of Gastrointestinal Oncology

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1948-5204

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

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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. Dec 15, 2026; 18(12): 123488
Published online Dec 15, 2026. doi: 10.4251/wjgo.123488

Up-regulation of protein C contributes to the progression of gastric cancer by modulating the MDM2/p53 axis

Liu Wang, Tian-Yi Fang, Jia-Liang Gao, Yu-Fei Wang, Hong-Wei Li, Ying-Wei Xue

Liu Wang, Harbin Medical University Cancer Hospital, Harbin 150000, Heilongjiang Province, China

Tian-Yi Fang, Jia-Liang Gao, Ying-Wei Xue, Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China

Yu-Fei Wang, Hong-Wei Li, Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China

Author contributions: Wang L designed and conceived the project, performed data collection, analysis, and interpretation, conducted experiments, and wrote the manuscript; Fang TY and Gao JL contributed to data acquisition, analysis, and interpretation; Wang YF and Li HW participated in patient data collection and experimental work; Xue YW critically revised the manuscript for important intellectual content; all authors reviewed and approved the final manuscript and agreed to be accountable for all aspects of the work.

AI contribution statement: This manuscript was edited using AI tools solely for language refinement.

Supported by the Nn10 Program of Harbin Medical University Cancer Hospital, China, No. Nn10 PY 2017-03.

Institutional review board statement: All study participants or their legal guardians provided signed informed consent forms. All the followed procedures were performed according to the ethical standards of the Human Subjects Responsibility Committee (institutions and countries), as well as the 1964 Helsinki Declaration and subsequent editions. This research was approved by Harbin Medical University Cancer Hospital Ethics Committee (No. 2019-198-R).

Institutional animal care and use committee statement: All animal experiments were performed following the guidelines for the Care and Use of Laboratory Animals. All animal-related procedures were approved by Harbin Medical University Cancer Hospital Animal Ethics Committee (No. 2019-164-R).

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

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 Harbin Medical University Gastric Cancer cohort was stored in the Gene Expression Omnibus repository (GSE184336 and GSE179252). All relevant patient data were stored in the Gastric Cancer Information Management System v1.2 of Harbin Medical University Cancer Hospital (Copyright No. 2013SR087424).

Corresponding author: Ying-Wei Xue, MD, Doctor, Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin 150081, Heilongjiang Province, China. xueyingwei@hrbmu.edu.cn

Received: May 20, 2026
Revised: August 8, 2026
Accepted: October 13, 2026
Published online: December 15, 2026
Processing time: 174 Days and 2.7 Hours

Abstract

BACKGROUND

Gastric cancer remains a major global health burden, and reliable prognostic biomarkers to guide therapeutic strategies are still lacking. Previous studies have revealed that protein C (PROC) participates in the progression of several malignancies, yet its biological function and prognostic value in gastric cancer have not been fully elucidated. Although the MDM2/p53 signaling axis is critical for gastric tumorigenesis, the regulatory relationship between PROC and this pathway has not been characterized.

AIM

To investigate the expression, prognostic significance, and mechanistic role of PROC in GC progression, with a focus on its interaction with the MDM2/p53 axis.

METHODS

Differential expression analysis was performed using transcriptomic data from GC patients stratified by survival. PROC expression was validated in 180 paired GC and adjacent tissues using immunohistochemistry, and in The Cancer Genome Atlas and Harbin Medical University Gastric Cancer datasets. In vitro assays, including proliferation, colony formation, migration, invasion, and apoptosis, were conducted in PROC-knockdown GC cell lines. Pathway enrichment and western blotting were used to explore downstream signaling. Xenograft models were established to confirm in vivo effects.

RESULTS

PROC was significantly upregulated in GC tissues and associated with poor overall survival across independent cohorts. Silencing PROC in MKN1 and MKN45 cells reduced proliferation, colony formation, migration, and invasion, while enhancing apoptosis. Transcriptomic and biochemical analyses revealed that PROC knockdown restored p53 activity by downregulating MDM2, leading to increased pro-apoptotic signaling. In xenograft models, PROC depletion markedly inhibited tumor growth and activated the p53 pathway.

CONCLUSION

In p53 wild-type GC cells, PROC acts as an oncogenic driver by modulating the MDM2/p53 axis, promoting tumor progression. Targeting PROC may represent a novel therapeutic approach and prognostic biomarker in GC.

Keywords: Gastric cancer; Protein C; MDM2/p53 axis; The Cancer Genome Atlas; Transcriptome

Core Tip: Protein C (PROC) is upregulated in gastric cancer (GC) and acts as an oncogenic driver by modulating the MDM2/p53 axis to promote tumor proliferation, metastasis, and poor survival. Targeting PROC restores p53 activity and suppresses tumor growth, offering a novel therapeutic strategy and prognostic biomarker for GC.