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World J Gastroenterol. Sep 21, 2026; 32(35): 119277
Published online Sep 21, 2026. doi: 10.3748/wjg.119277
Matrix metalloproteinase 3 facilitates colorectal cancer progression by enhancing cell proliferation and invasion
Bin-Bin Du, Zheng-Peng Qian, Cheng-Zhang Zhu, Quan-Lin Guan
Bin-Bin Du, Quan-Lin Guan, The First School of Clinical Medical, Lanzhou University, Lanzhou 730000, Gansu Province, China
Zheng-Peng Qian, Cheng-Zhang Zhu, Department of Anorectal Medicine, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
Co-first authors: Bin-Bin Du and Zheng-Peng Qian.
Co-corresponding authors: Cheng-Zhang Zhu and Quan-Lin Guan.
Author contributions: This work was collaboratively performed by the authors, whose contributions are clearly defined as follows. Du BB proposed the core research concept, designed the overall methodology, performed the investigation and formal data analysis, drafted the original manuscript, and critically revised the manuscript. Qian ZP optimized and validated the research methodology, verified the experimental results, curated the research data, participated in drafting the original manuscript, and checked and verified the biostatistical analysis. Du BB and Qian ZP made substantial, equal and indispensable contributions to the study and are therefore designated co-first authors. Guan QL supervised the entire research process, acquired research funding, managed project implementation, provided key guidance on study design and data interpretation, and comprehensively revised the manuscript to ensure academic quality. Zhu CZ oversaw the overall project progress, coordinated the research work, offered critical insights into result analysis and academic logic, and participated in manuscript review, editing and finalization. Guan QL and Zhu CZ made equivalent, complementary and decisive contributions throughout the study and are designated co-corresponding authors. All authors have read and approved the final version of the manuscript.
AI contribution statement: No ChatGPT, Grammarly, DeepL, or any other AI tools of any type were used in any link related to the manuscript, including but not limited to research design, data collection, manuscript writing, and revision. The entire main text of the manuscript, including the Abstract, Introduction, Materials and Methods, Results, Discussion, and Conclusion, was independently written by the authors through their own research and analysis, without any involvement of AI tools in the generation of any part of the content. All language polishing, translation work, data analysis, and writing assistance related to the manuscript were completed manually by the authors and the research team. No AI tools were used for any of the above links to ensure the accuracy and authenticity of the content. The study design, research route formulation, and the interpretation of all research results were independently completed by the authors based on professional knowledge and research practice. AI tools did not participate in any decision-making or interpretation process related to the study. All images included in the manuscript are original images obtained through actual research experiments, data visualization, or authorized and standardized sources. None of the images were generated, modified, or processed by AI tools. We confirm that all content of the manuscript is original work completed by the authors, and no AI tools were used in any link of the manuscript creation and research process. We shall bear all responsibilities for the authenticity and originality of the manuscript.
Supported by Department of Health Commission of Gansu Province, No. GSWSKY2024-12; and Gansu Provincial Administration of Traditional Chinese Medicine, No. GZKJ-2024-64.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board (IRB) of Gansu Provincial Hospital, No. 2025-341. The study protocol was in full compliance with the Declaration of Helsinki and relevant ethical guidelines for medical research involving human subjects/animals. Informed consent was obtained from all participants prior to their involvement in the study, and all participants had the right to withdraw from the study at any time without any negative consequences.
Institutional animal care and use committee statement: All animal experimental procedures were sanctioned by the Bestcell Model Biological Center (IACUC Issue No. 2025-08-28C).
Conflict-of-interest statement: 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 proteomics datasets generated and analyzed in the current study are available in the Integrated Proteome Resources repository, Project ID: IPX0014228000. The designated point of contact for data requests: Dr. Bin-Bin Du (dubb2005@163.com).
Corresponding author: Quan-Lin Guan, PhD, Chief, Professor, The First School of Clinical Medical, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, Gansu Province, China. guanql@lzu.edu.cn
Received: January 23, 2026
Revised: February 6, 2026
Accepted: March 27, 2026
Published online: September 21, 2026
Processing time: 208 Days and 9.7 Hours
Abstract
BACKGROUND

Matrix metalloproteinase 3 (MMP3) plays critical roles in tumor progression, but its function in colorectal cancer (CRC) remains incompletely understood.

AIM

To investigate MMP3 expression, its clinical significance, and molecular mechanisms in CRC.

METHODS

The Cancer Genome Atlas colon adenocarcinoma and rectal adenocarcinoma datasets were analyzed for MMP3 mRNA levels, which were then validated in 40 paired CRC tumor and adjacent normal tissues (via quantitative real-time-PCR) and 90 CRC cases (via immunohistochemistry). Clinicopathological correlation analysis and Kaplan-Meier survival analysis were performed. The biological functions of MMP3 were assessed using gain-and loss-of-function assays in CRC cell lines (SW480, SW620, HT-29, HCT116, LOVO) and the normal human colonic epithelial cell line NCM460. 4D-data independent acquisition proteomics was used to identify downstream targets of MMP3, which were validated by quantitative real-time-PCR and xenograft models.

RESULTS

MMP3 was significantly upregulated in CRC tissues compared with normal tissues and correlated with advanced tumor size, nerve invasion, T stage, lymph node metastasis, tumor-node-metastasis stage, and poor 5-year overall survival. MMP3 knockdown inhibited CRC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis; MMP3 overexpression exerted the opposite effects. Proteomic analysis identified endothelial PAS domain protein 1 (EPAS1) as a key downstream target of MMP3. In CRC xenograft models, MMP3 silencing reduced EPAS1 expression and suppressed tumor growth.

CONCLUSION

Our findings demonstrate that MMP3 promotes CRC progression by regulating EPAS1, highlighting MMP3 as a potential prognostic biomarker and therapeutic target for CRC.

Keywords: Matrix metalloproteinase 3; Colorectal cancer; Endothelial PAS domain protein 1; Tumor progression; Biomarker

Core Tip: Matrix metalloproteinase 3 (MMP3) is significantly overexpressed in colorectal cancer (CRC) tissues and cells, which is closely associated with advanced tumor stage, lymph node metastasis, nerve invasion and worse overall survival. Functional experiments demonstrate that MMP3 promotes CRC cell proliferation, migration, and invasion and represses apoptosis. Using proteomic analysis and in vivo xenograft models, we identify and verify endothelial PAS domain protein 1 (EPAS1) as a critical downstream target of MMP3. MMP3 facilitates CRC progression by regulating EPAS1 expression, suggesting that MMP3 may serve as a novel prognostic biomarker and potential therapeutic target for CRC.

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