Articles

Downregulation of GMPS inhibited the proliferation of hepatocellular cancer cells via the regulation of STAT3/c-Myc pathway

Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 15 June 2026
9
Views
3
Downloads

Authors

Hepatocellular cancer (HCC) is the sixth most common type of cancer worldwide. Guanosine monophosphate synthase (GMPS) participates in the regulation of chromatin and genes in various organisms, and is highly expressed in a number of human malignant tumors. However, the role of GMPS in HCC has not yet been fully studied and clarified. In this study, the differential fold changes in gene expression levels between HCC cancer tissues and correspondent adjacent normal tissue in The Cancer Genome Atlas Program and GEO datasets were analyzed using R language. GMPS expression levels in HCC cells were knocked down using specific siRNAs. In addition, CCK-8, EdU, TUNEL and immunofluorescence staining were conducted to explore the effects of GMPS siRNAs on HCC cell viability, proliferation, apoptosis and the STAT pathway level, respectively. The results indicated GMPS expression was significantly increased in HCC tumor tissues compared with the corresponding adjacent normal tissues. In addition, high expression of GMPS is negatively associated with the survival rate of patients with HCC. In vitro studies illustrated the knockdown of GMPS notably prevented HCC cell proliferation and induced HCC cell (Hep3B2.1-7 and MHCC97H) apoptosis by regulating the STAT3/c-Myc pathway. The apoptosis-specific marker cleaved caspase was significantly upregulated by GMPS knockdown in HCC cells. The findings of the present study revealed the association between GMPS and the prognosis of HCC. The results suggested that GMPS may serve as a promising marker for the prognosis of HCC, and it may also be a potential therapeutic target for HCC. These findings may lay the theoretical foundation for the clinical application of GMPS.

Downloads

Download data is not yet available.

Citations

1. McGlynn KA, Petrick JL, Groopman JD. Liver cancer: progress and priorities. Cancer Epidemiol Biomarkers Prev 2024;33:1261-72. DOI: https://doi.org/10.1158/1055-9965.EPI-24-0686
2. Zhou J, Sun H, Wang Z, Cong W, Zeng M, Zhou W, et al. Guidelines for the diagnosis and treatment of primary liver cancer (2022 edition). Liver Cancer 2023;12:405-44. DOI: https://doi.org/10.1159/000530495
3. Welin M, Lehtiö L, Johansson A, Flodin S, Nyman T, Trésaugues L, et al. Substrate specificity and oligomerization of human GMP synthetase. J Mol Biol 2013;425:4323-33. DOI: https://doi.org/10.1016/j.jmb.2013.06.032
4. Huang PS, Wang LY, Wang YW, Tsai MM, Lin TK, Liao CJ, et al. Evaluation and application of drug resistance by biomarkers in the clinical treatment of liver cancer. Cells 2023;12:869. DOI: https://doi.org/10.3390/cells12060869
5. Maomao C, He L, Dianqin S, Siyi H, Xinxin Y, Fan Y, et al. Current cancer burden in China: epidemiology, etiology, and prevention. Cancer Biol Med 2022;19:1121-38. DOI: https://doi.org/10.20892/j.issn.2095-3941.2022.0231
6. Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL. The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families. Nat Struct Biol 1996;3:74-86. DOI: https://doi.org/10.1038/nsb0196-74
7. Hirst M, Haliday E, Nakamura J, Lou L. Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA. J Biol Chem 1994;269:23830-7. DOI: https://doi.org/10.1016/S0021-9258(17)31590-9
8. Wang J, Wu Y, Li Y, Wang Y, Shen F, Zhou J, et al. Guanosine monophosphate synthase upregulation mediates cervical cancer progression by inhibiting the apoptosis of cervical cancer cells via the Stat3/P53 pathway. Int J Oncol 2021;58:3. DOI: https://doi.org/10.3892/ijo.2021.5183
9. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene 2006;25:4633-46. DOI: https://doi.org/10.1038/sj.onc.1209597
10. Ballut L, Violot S, Kumar S, Aghajari N, Balaram H. GMP synthetase: allostery, structure, and function. Biomolecules 2023;13:1379. DOI: https://doi.org/10.3390/biom13091379
11. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015;43:e47. DOI: https://doi.org/10.1093/nar/gkv007
12. Zhang P, Li X, He Q, Zhang L, Song K, Yang X, et al. TRIM21-SERPINB5 aids GMPS repression to protect nasopharyngeal carcinoma cells from radiation-induced apoptosis. J Biomed Sci 2020;27:30. DOI: https://doi.org/10.1186/s12929-020-0625-7
13. Reddy BA, van der Knaap JA, Bot AG, Mohd-Sarip A, Dekkers DH, Timmermans MA, et al. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell 2014;53:458-70. DOI: https://doi.org/10.1016/j.molcel.2013.12.017
14. Guo T, Liu L, Zeng L, Yang Y, Song T, Zhao H, et al. GMPS inhibits the proliferation and migration of non-small cell lung cancer via the regulation of the DNMT 1/SERPINB2 axis. Cell Oncol (Dordr) 2025;48:1145-58. DOI: https://doi.org/10.1007/s13402-025-01078-1
15. Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell 2011;147:742-58. DOI: https://doi.org/10.1016/j.cell.2011.10.033
16. Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D'Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY) 2016;8:603-19. DOI: https://doi.org/10.18632/aging.100934
17. Su X, Feng C, Wang S, Shi L, Gu Q, Zhang H, et al. The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53. Cell Death Differ 2021;28:2450-64. DOI: https://doi.org/10.1038/s41418-021-00762-7
18. Liu Y, Xu Q, Deng F, Zheng Z, Luo J, Wang P, et al. HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway. J Exp Clin Cancer Res 2023;42:38. DOI: https://doi.org/10.1186/s13046-023-02609-0
19. Li Y, Dong Y. TTI-101 targets STAT3/c-Myc signaling pathway to suppress cervical cancer progression: an integrated experimental and computational analysis. Cancer Cell Int 2024;24:286. DOI: https://doi.org/10.1186/s12935-024-03463-6
20. Saegusa M, Takano Y, Kishimoto H, Wakabayashi G, Nohga K, Okudaira M. Comparative analysis of p53 and c-myc expression and cell proliferation in human hepatocellular carcinomas--an enhanced immunohistochemical approach. J Cancer Res Clin Oncol 1993;119:737-44. DOI: https://doi.org/10.1007/BF01195346

CRediT authorship contribution

Lin Liua, Wei Huang, methodology, writing – original draft. Yu Wu, Guanlong Yea, Jing Zhanga, Tong Shen, investigation, data collection and analysis. Changjuan Ouyang, supervision, validation, writing – original draft. All authors have read and approved the final version of the manuscript.

Data Availability Statement

The data generated in the present study may be requested from the corresponding author.

How to Cite



1.
Guo Z, Yu J, Sun J, Yang S, Pu J. Downregulation of GMPS inhibited the proliferation of hepatocellular cancer cells via the regulation of STAT3/c-Myc pathway. Eur J Histochem [Internet]. 2026 Jun. 15 [cited 2026 Jun. 17];70(2). Available from: https://www.ejh.it/ejh/article/view/4541