Abstract
TNFRSF19 is a member of the tumor necrosis factor receptor superfamily, and its function exhibits variability among different types of cancers. The influence of TNFRSF19 on triple-negative breast cancer (TNBC) has yet to be definitively established. In this study, bioinformatics analyses revealed that lower TNFRSF19 was associated with the poorer prognosis, higher lymph node metastasis and lower immune infiltration. Subsequently, data obtained from the TCGA database and collection of tissue samples revealed that the mRNA and protein expression levels of TNFRSF19 were observed to be significantly reduced in TNBC tissue compared to normal tissue. Additionally, the results of in vitro experiments have demonstrated that TNFRSF19 possessed the ability to inhibit the proliferation, migration and invasive capabilities of TNBC cells. In vivo trials elucidated that TNFRSF19 could suppress tumor xenografts growth. Mechanistically, TNFRSF19 initiated caspase-independent cell death and induced paraptosis. Moreover, rescue assays demonstrated that TNFRSF19 induced-paraptosis was facilitated by MAPK pathway-mediated endoplasmic reticulum (ER) stress. In conclusion, our findings demonstrated that the upregulation of TNFRSF19 functioned as a tumor suppressor in TNBC by stimulating paraptosis through the activation of the MAPK pathway-mediated ER stress, highlighting its potential to be a new therapeutic target for TNBC.
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Acknowledgements
All authors are grateful to each participant involved in this study. We appreciate the support from two pathologists (Dr. Ge Wang and Dr. Shengwei Mo).
Funding
This research was funded by National Natural Science Foundation of China (Grant No 21834002).
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SL: analyzed data, performed software, in vitro/in vivo trials and draft the manuscript. YT: reviewing and in vivo trials. CL: visualization. TY and ZG: data collection and figure preparation. LZ: conceptualization, discussed analysis and resources.
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The Institutional Animal Care and Use Committee of Tongji Medical College, Huazhong University of Science and Technology granted approval for all animal experiments. The Ethics Committee of Wuhan Tongji Hospital granted approval for the collection of patients’ samples, and informed consent forms were obtained from the patients prior to sample collection.
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Liu, S., Tian, Y., Liu, C. et al. TNFRSF19 promotes endoplasmic reticulum stress-induced paraptosis via the activation of the MAPK pathway in triple-negative breast cancer cells. Cancer Gene Ther 31, 217–227 (2024). https://doi.org/10.1038/s41417-023-00696-x
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DOI: https://doi.org/10.1038/s41417-023-00696-x