Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2025; 17(6): 105160
Published online Jun 15, 2025. doi: 10.4251/wjgo.v17.i6.105160
Identification and validation of extracellular matrix-related genes in the progression of gastric cancer with intestinal metaplasia
Lu Wang, Meng-Han Wang, Yao-Hong Yuan, Rui-Ze Xu, Lu Bai, Mi-Zhu Wang
Lu Wang, Lu Bai, Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
Meng-Han Wang, Yao-Hong Yuan, Rui-Ze Xu, Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
Mi-Zhu Wang, Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
Co-first authors: Lu Wang and Meng-Han Wang.
Author contributions: Wang L, Wang MH and Yuan YH designed the research study and completed the analysis; Xu RZ and Bai L completed the specimen collection and experimental process; Wang MZ completed the manuscript review and revisions; All authors read and approved the final manuscript.
Supported by the Inner Mongolia Autonomous Region Health Science and Technology Program, No. 202201441; and Qingmiao Plan of Baotou Medical College, No. BYJJ-ZRQM202230.
Institutional review board statement: The study was reviewed and approved by the local Ethics Committee of The Second Affiliated Hospital of Baotou Medical College (Approval No. 2024-ZX-057).
Institutional animal care and use committee statement: This study does not involve any animal experiments.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: The datasets supporting this research include GSE191275, GSE15459 and the Cancer Genome Atlas-stomach adenocarcinoma dataset. GSE191275 and GSE15459 are available from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo); The Cancer Genome Atlas-stomach adenocarcinoma is available from the Cancer Genome Atlas database (https://www.cancer.gov/ccg/research/genome-sequencing/tcga).
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: Mi-Zhu Wang, MD, Chief Physician, Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, No. 30 Hude Mulin Street, Qingshan District, Baotou 300000, Inner Mongolia Autonomous Region, China. wangmizhu2008@163.com
Received: January 14, 2025
Revised: March 31, 2025
Accepted: April 23, 2025
Published online: June 15, 2025
Processing time: 151 Days and 8.5 Hours
Abstract
BACKGROUND

Gastric cancer (GC) is a highly lethal malignancy with a high incidence and mortality rate globally. Its development follows the Correa model, with intestinal metaplasia (IM) being a critical precursor to GC. However, the mechanisms underlying IM progression to GC remain unclear. This study explored extracellular matrix (ECM)-related gene changes during IM progression to GC, aiming to identify biomarkers that could improve early diagnosis and treatment strategies for GC, ultimately enhancing patient outcomes.

AIM

To analyze transcriptome sequencing data, molecular biomarkers that can predict GC risk and monitor IM progression can be identified, providing new insights and strategies for preventing IM-GC transformation.

METHODS

Weighted gene co-expression network analysis served for confirming gene modules. Upregulated ECM-related genes were further tested using univariate Cox regression and least absolute shrinkage and selection operator analysis to select hub genes and construct a survival analysis model. The intestinal cell model was established by stimulating GES-1 cells with chenodeoxycholic acid.

RESULTS

Weighted gene co-expression network analysis identified 1709 differentially expressed genes from the GSE191275 dataset, while The Cancer Genome Atlas stomach adenocarcinoma revealed 4633 differentially expressed genes. The intersection of these datasets identified 71 upregulated and 171 downregulated genes, which were enriched in ECM-related pathways. Univariate Cox regression analysis identified six genes with prognostic significance, and least absolute shrinkage and selection operator regression pinpointed secreted protein acidic and rich in cysteine (SPARC) and SERPINE1 as non-zero coefficient genes. A prognostic model integrating clinical tumor node metastasis staging, age, SERPINE1, and SPARC was constructed. Immunohistochemistry analysis confirmed an increasing expression of SPARC protein from normal gastric mucosa (-), to IM (+- to +), and to GC (+ to ++), with significant differences (P < 0.05). Western blot analysis demonstrated significantly higher SPARC expression in induced intestinal cells compared to GES-1. Furthermore, after SPARC knockdown in the human GC cell line HGC27, cell counting kit-8 and colony formation assays showed a reduction in cell proliferative ability, while the wound healing assay revealed impaired cell migration capacity.

CONCLUSION

Comprehensive analysis suggested that a model incorporating clinical tumor node metastasis staging, age, and SPARC/SERPINE1 expression served as a prognostic predictor for GC. Moreover, elevated SPARC expression in IM and GC suggests its potential as a proper biomarker to detect GC in early stage and as a novel therapeutic target, guiding clinical applications.

Keywords: Gastric cancer; Intestinal metaplasia; Extracellular matrix; SPARC; SERPINE1

Core Tip: This study aimed to identify molecular biomarkers for predicting gastric cancer (GC) risk and monitoring intestinal metaplasia progression. Using weighted gene co-expression network analysis, 71 upregulated and 171 downregulated genes related to the extracellular matrix were identified. Secreted protein acidic and rich in cysteine (SPARC) and SERPINE1 were found to be significant prognostic genes. A survival model integrating clinical tumor node metastasis staging, age, and SPARC/SERPINE1 expression was developed. Immunohistochemistry and western blot analyses confirmed the elevated expression of SPARC in intestinal metaplasia and GC. SPA0RC expression correlated with cancer progression and could serve as an early biomarker and therapeutic target for GC.