Finding New Biomarkers and Therapeutic Targets for Gastric Cancer Using a System Biology Approach

Document Type : Research/Original Article

Author

Faculty of Medicinal Plants, Amol University of Special Modern Technologies, Amol, Mazandaran, Iran

10.30476/acrr.2025.108420.1257

Abstract

Background: Gastric cancer is one of the leading causes of cancer-related mortality worldwide, with
approximately one million new cases diagnosed annually. Identifying key genes involved in this cancer is
crucial for proposing suitable therapeutic targets and facilitating early diagnosis. This study aims to analyze
the transcriptomic profile of gastric cancer cells to identify these critical genes.
Methods: Gene expression profiles from six gastric cancer datasets (GSE13911, GSE79973, GSE103236,
GSE116312, GSE118916, and GSE161533) were analyzed. Differentially expressed genes were identified, and
their protein-protein interaction networks were investigated using graph-based analysis.
Results: Transcriptome analysis of gastric cancer versus normal tissues identified 516 significantly differentially
expressed genes. Among these, three genes, ATP4A, SPP1, and GKN1, were prioritized as potential biomarkers
based on their significant expression changes (log2 fold change of 6.76, 3.5, and 6.88, respectively ; p-value=0.01)
and central roles in the protein-protein interaction network, with node degrees of 17, 22, and 11.
Conclusion: The combination of SPP1, ATP4A, and GKN1 provides a powerful and minimally invasive tool for
diagnosing gastric cancer. This multi-marker approach utilizes the gastric specificity of ATP4A and GKN1 for
early detection, alongside the malignant indicator SPP1, to effectively distinguish gastric cancer from benign
conditions, thereby reducing false positives.

Keywords


Ricci AD, Rizzo A, Brandi G. DNA
damage response alterations in gastric
cancer: Knocking down a new wall.
Future Medicine; 2021. p. 865-8.
2. Alagesan P, Goodwin JC, Garman
KS, Epplein M. Cancer progress and
priorities: gastric cancer. Cancer
Epidemiology, Biomarkers &
Prevention. 2023;32(4):473-86.
3. Yang W-J, Zhao H-P, Yu Y, Wang
J-H, Guo L, Liu J-Y, et al. Updates
on global epidemiology, risk and
prognostic factors of gastric cancer.
World journal of gastroenterology.
2023;29(16):2452.
4. Rugge M, Fassan M, Graham DY.
Epidemiology of gastric cancer.
Gastric cancer: principles and
practice. 2015:23-34.
5. Matsuoka T, Yashiro M. Biomarkers
of gastric cancer: Current topics and
future perspective. World journal of
gastroenterology. 2018;24(26):2818.
6. Necula L, Matei L, Dragu D, Neagu
AI, Mambet C, Nedeianu S, et al.
Recent advances in gastric cancer
early diagnosis. World journal of
gastroenterology. 2019;25(17):2029.
7. Desai S, Guddati A K.
Carcinoembr yonic antigen,
carbohydrate antigen 19-9, cancer
antigen 125, prostate-specific
antigen and other cancer markers:
a primer on commonly used cancer
markers. World Journal of Oncology.
2023;14(1):4.
8. Wu D, Zhang P, Ma J, Xu J, Yang L,
Xu W, et al. Serum biomarker panels
for the diagnosis of gastric cancer.
Cancer medicine. 2019;8(4):1576-83.
9. Sohn BH, Hwang J-E, Jang H-J,
Lee H-S, Oh SC, Shim J-J, et
al. Clinical significance of four
molecular subtypes of gastric cancer
identified by the cancer genome atlas
project. Clinical Cancer Research.
2017;23(15):4441-9.
10. Jin S, Wang J, Wang K. A
Comprehensive Analysis of the
Clinical Significance and Underlying
Oncogenic Roles of Specific MMPs
in Gastric Carcinoma Reveals
their Potential Roles in Prognosis
and Therapy. Current Molecular
Medicine. 2025.
11. Xu M-d, Dong L, Qi P, Weng W-w,
Shen X-h, Ni S-j, et al. Pituitary
tumor-transforming gene-1 serves as
an independent prognostic biomarker
for gastric cancer. Gastric Cancer.
2016;19:107-15.
12. Chevriau J, De Palma GZ, Jozefkowicz
C, Vitali V, Canessa Fortuna A, Ayub
N, et al. Permeation mechanisms of
hydrogen peroxide and water through
Plasma Membrane Intrinsic Protein
aquaporins. Biochemical Journal.
2024;481(19):1329-47.
13. Cao D, Zhao D, Jia Z, Su T, Zhang
Y, Wu Y, et al. Reactivation of Atp4a
concomitant with intragenic DNA
demethylation for cancer inhibition in
a gastric cancer model. Life sciences.
2020;242:117214.
14. Engevik AC, Kaji I, Goldenring
JR. The physiology of the gastric
parietal cell. Physiological reviews.
2020;100(2):573-602.
15. Junnila S, Kokkola A, Mizuguchi T,
Hirata K, Karjalainen‐Lindsberg ML,
Puolakkainen P, et al. Gene expression
analysis identifies over‐expression of
CXCL1, SPARC, SPP1, and SULF1 in
gastric cancer. Genes, Chromosomes
and Cancer. 2010;49(1):28-39.
16. Choe EK, Yi JW, Chai YJ, Park KJ.
Upregulation of the adipokine genes
ADIPOR1 and SPP1 is related to
poor survival outcomes in colorectal
cancer. Journal of surgical oncology.
2018;117(8):1833-40.
17. Zeng B, Zhou M, Wu H, Xiong
Z. SPP1 promotes ovarian cancer
progression via Integrin β1/FAK/AKT
signaling pathway. OncoTargets and
therapy. 2018:1333-43.
18. Göthlin Eremo A, Lagergren K,
Othman L, Montgomery S, Andersson
G, Tina E. Evaluation of SPP1/
osteopontin expression as predictor
of recurrence in tamoxifen treated
breast cancer. Scientific reports.
2020;10(1):1451.
19. Tang H, Chen J, Han X, Feng Y, Wang
F. Upregulation of SPP1 is a marker
for poor lung cancer prognosis and
contributes to cancer progression
and cisplatin resistance. Frontiers
in cell and developmental biology.
2021;9:646390.
20. Pang X, Xie R, Zhang Z, Liu Q, Wu
S, Cui Y. Identification of SPP1 as
an extracellular matrix signature
for metastatic castration-resistant
prostate cancer. Frontiers in oncology.
2019;9:924.
21. Yoon JH, Park YG, Nam SW, Park
WS. The diagnostic value of serum
gastrokine 1 (GKN1) protein in
gastric cancer. Cancer Medicine.
2019;8(12):5507-14.
22. Xing R, Li W-M, Cui J-T, Xia N, Lu
Y-Y. GKN1 inhibits cell invasion in
gastric cancer by inactivating the
NF-kappaB pathway. Discovery
medicine. 2015;19(103):65-71.
23. Yan GR, Xu SH, Tan ZL, Yin XF,
He QY. Proteomics characterization
of gastrokine 1‐induced growth
inhibition of gastric cancer cells.
Proteomics. 2011;11(18):3657-64.