AccScience Publishing / EJMO / Volume 8 / Issue 3 / DOI: 10.14744/ejmo.2024.97176
RESEARCH ARTICLE

Expression of Trx-1, HIF-1α, and Their Associations with Clinicopathological Parameters in Gastric Cancer

Guangcai Niu1 Anqiang Feng2
Show Less
1 Department of Gastrointestinal Surgery, Xuzhou Central Hospital, Xuzhou, China
2 Department of Gastroenterology, Xuzhou Central Hospital, Xuzhou, China
EJMO 2024, 8(3), 371–377; https://doi.org/10.14744/ejmo.2024.97176
Submitted: 4 February 2024 | Accepted: 19 June 2024 | Published: 10 September 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

Objectives: Thioredoxin-1 (Trx-1) is a small redox protein that plays an important role in many biological processes. Although increased expression of Trx-1 in various solid tumors has been reported, its clinical significance and diagnostic value in human gastric cancer (GC) are not well defined. Hypoxia-inducible factor-1α (HIF-1α) is actively involved in the metabolism of many tumors; however, the relationship between its expression levels and clinical significance in GC still needs to be established.

Methods: In this study, the levels of HIF-1α and Trx-1 mRNA and protein in 20 freshly frozen GC and matched normal tissues were determined by quantitative PCR (qPCR). Additionally, an immunohistochemistry assay was performed to measure the protein levels of Trx-1 and HIF-1α in 162 GC samples.

Results: We observed that the Trx-1 mRNA and protein levels increased significantly in GC tissues, while that of HIF-1α also increased, and both were associated with a poor prognosis (p<0.001). Multivariate analysis revealed that Borrmann type, Trx-1, and HIF-1α were independent predictors of GC prognosis (p<0.001).

Conclusion: Our results indicate that both Trx-1 and HIF-1α may be promising prognostic indicators and therapeutic targets for GC patients. 

 
Keywords
Gastric cancer
Trx-1
HIF-1α
prognosis
Conflict of interest
None declared.
References

1. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet 2020;396:635–48. 

2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49. 

3. Kruszyna Ł, Murawa D, Jagodziński PP, Oszkinis G, Krasiński Z. The expression and prognostic significance of VEGF and CXCR4 in gastric cancer: Correlation with angiogenesis, lymphangiogenesis and progression. Curr Issues Mol Biol 2022;44:3075–88. 

4. Wang J, Dong Z, Sheng Z, Cai Y. Hypoxia-induced PVT1 promotes lung cancer chemoresistance to cisplatin by autophagy via PVT1/miR-140-3p/ATG5 axis. Cell Death Discov 2022;8:104. 

5. Natarajan SR, Ponnusamy L, Manoharan R. MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKα1/mTOR/HIF-1α signaling pathway. Biochim Biophys Acta Mol Cell Res 2022;1869:119242. 

6. Zhang J, Du C, Zhang L, Wang Y, Zhang Y, Li J. LncRNA LINC00649 promotes the growth and metastasis of triplenegative breast cancer by maintaining the stability of HIF-1α through the NF90/NF45 complex. Cell Cycle 2022;21:1034–47. 

7. Chai X, Wu X, Ren J, Du K, Wu X, Feng F, et al. Expression of HIF-1α, ANXA3, CD133 and their associations with clinicopathological parameters in human colon carcinoma. Transl Cancer Res 2022;11:1644–51. 

8. Jiang X, Zhang S, Yin Z, Sheng Y, Yan Q, Sun R, et al. The correlation between NEDD4L and HIF-1α levels as a gastric cancer prognostic marker. Int J Med Sci 2019;16:1517–24. 

9. Lee BL, Kim WH, Jung J, Cho SJ, Park JW, Kim J, et al. A hypoxiaindependent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer. Carcinogenesis 2008;29:44–51. 

10. Ribback S, Winter S, Klatte T, Schaeffeler E, Gellert M, Stühler V, et al. Thioredoxin 1 (Trx1) is associated with poor prognosis in clear cell renal cell carcinoma (ccRCC): An example for the crucial role of redox signaling in ccRCC. World J Urol 2022;40:739–46. 

11. Hoflehner E, Binder M, Hemmer W, Mahler V, Panzani RC, Jarisch R, et al. Thioredoxin from the Indianmeal moth Plodia interpunctella: Cloning and test of the allergenic potential in mice. PLoS One 2012;7:e42026. 

12. Shang W, Xie Z, Lu F, Fang D, Tang T, Bi R, et al. Increased thioredoxin-1 expression promotes cancer progression and predicts poor prognosis in patients with gastric cancer. Oxid Med Cell Longev 2019;2019:9291683. 

13. Watanabe R, Nakamura H, Masutani H, Yodoi J. Anti-oxidative, anti-cancer and anti-inflammatory actions by thioredoxin 1 and thioredoxin-binding protein-2. Pharmacol Ther 2010;127:261–70. 

14. Hawkes HJ, Karlenius TC, Tonissen KF. Regulation of the human thioredoxin gene promoter and its key substrates: A study of functional and putative regulatory elements. Biochim Biophys Acta 2014;1840:303–14. 

15. Welsh SJ, Bellamy WT, Briehl MM, Powis G. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 2002;62:5089–95. 

16. Mao J, Liu J, Zhou M, Wang G, Xiong X, Deng Y. Hypoxia-induced interstitial transformation of microvascular endothelial cells by mediating HIF-1α/VEGF signaling in systemic sclerosis. PLoS One 2022;17:e0263369. 

17. Liu M, Du K, Jiang B, Wu X. High expression of PhospholipaseD2 induced by hypoxia promotes proliferation of colon cancer cells through activating NF- κ Bp65 signaling pathway. Pathol Oncol Res 2020 ;26:281–90. 

18. Guo R, Yang B. Hypoxia-induced LXRα contributes to the migration and invasion of gastric cancer cells. Folia Biol (Praha) 2021;67:91–101. 

19. Gao S, Wang Z, Liu X, Xu B, Liu F. The calcimedin annexin A3 displays tumor-promoting effect in esophageal squamous cell carcinoma by activating NF-κB signaling. Mamm Genome 2021;32:381–8. 

20. Balta E, Janzen N, Kirchgessner H, Toufaki V, Orlik C, Liang J, et al. Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment. Front Immunol 2022;13:1063313. 

Share
Back to top
Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing