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Thioredoxin reductase 3 suppression promotes colitis and carcinogenesis via activating pyroptosis and necrosis

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Abstract

Background

Txnrd3 as selenoprotein plays key roles in antioxidant process and sperm maturation. Inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease, are becoming significantly increasing disease worldwide in recent years which are proved relative to diet, especially selenium intake.

Methods

In the present study, 8-week-old C57BL/6N male Txnrd3-/-, Txnrd3-/ + , Txnrd3 + / + mice, weight 25–30 g, were randomly chosen and each group with 30 mice. Feed 3.5% DSS drinking water and normal water continuously for 7 days. Mouse colon cancer cells (CT26) were cultured in vitro to establish Txnrd3 overexpressed/knocked-down model by cell transfection technology. Morphology and ultrastructure, calcium levels, ROS level, cell death were observed and detected in vivo and vitro.

Results

In Txnrd3-/-mice, ulcerative colitis was more severe, the morphological and ultrastructural lesions were also more prominent compared with wild-type mice, accompanied by the significantly increased expression of NLRP3, Caspase1, RIPK3, and MLKL. Overexpression of Txnrd3 could lead to increased oxidative stress through intracellular calcium outflow-induced oxidative stress increase followed by necrosis and pyroptosis pathway activation and further inhibit the growth and proliferation of colon cancer cells.

Conclusion

Txnrd3 overexpression leads to intracellular calcium outflow and increased ROS, which eventually leads to necrosis and focal death of colon cancer cells, while causing Txnrd3-/- mice depth of the crypt deeper, weakened intestinal secretion and immune function and aggravate the occurrence of ulcerative colitis. The present study lays a foundation for the prevention and treatment of ulcerative colitis and colon carcinoma in clinic treatment.

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Availability of data and materials

All the data underlying this article are available in the article and in its online supplementary material.

Code availability

Manuscript was written using Microsoft Word 2010; Figures were achieved via Photoshop CS5. Data analysis and graph drawing were finished with Graphpad Prism 8.

Abbreviations

Selenium:

Se

Txnrd3:

Thioredoxin reductase 3

UC:

Ulcerative colitis

IBD:

Inflammatory bowel diseases

CRC:

Colorectal cancer

DSS:

Dextran sulfate sodium

siRNA:

Small interferring RNA

DAI:

Disease activity index

IOD:

Integrated Optical Density

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Acknowledgements

The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the Northeast Agricultural University. We would like to acknowledge the contributions and support of Pro. Shiwen Xu, Pro. Hongjin Lin and Dr. Mengrao Guo in present study.

Funding

This work was supported by the National Natural Science Foundation of China [grant number 31872531].

Author information

Authors and Affiliations

  1. College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People’s Republic of China

    Qi Liu, Pengyue Du, Yue Zhu, Xintong Zhang, Jingzeng Cai & Ziwei Zhang

  2. Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, People’s Republic of China

    Ziwei Zhang

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  1. Qi Liu
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  3. Yue Zhu
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  4. Xintong Zhang
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Contributions

Conceived and designed the experiments: Ziwei Zhang, Qi Liu. Performed the experiments: Qi Liu, Yue Zhu, Xintong Zhang. Analyzed the data: Pengyue Du, Jingzeng Cai. Contributed reagents /materials/analysis tools: Ziwei Zhang. Wrote the paper: Qi Liu.

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Correspondence to Ziwei Zhang.

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The authors declare no competing financial interests.

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Animal care and experimental procedures were performed with approval from the Northeast Agricultural University Institutional Animal Care and Use Committee.

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Liu, Q., Du, P., Zhu, Y. et al. Thioredoxin reductase 3 suppression promotes colitis and carcinogenesis via activating pyroptosis and necrosis. Cell. Mol. Life Sci. 79, 106 (2022). https://doi.org/10.1007/s00018-022-04155-y

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  • DOI: https://doi.org/10.1007/s00018-022-04155-y

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