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TNFRSF19 promotes endoplasmic reticulum stress-induced paraptosis via the activation of the MAPK pathway in triple-negative breast cancer cells

Cancer Gene Therapy volume 31, pages 217–227 (2024)Cite this article

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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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Fig. 1: Bioinformatic analysis of TNFRSF19 in breast cancer.
Fig. 2: Expression and function analysis of TNFRSF19 in TNBC.
Fig. 3: TNFRSF19 inhibits the proliferation, migration and invasion of TNBC cells.
Fig. 4: TNFRSF19 inhibits tumor growth of TNBC cells in vivo.
Fig. 5: TNFRSF19 induces paraptosis in TNBC cells.
Fig. 6: The induction of paraptosis by TNFRSF19 is mediated through MAPK pathway and ER stress.
Fig. 7: TNFRSF19 influence cell proliferation, migration and invasion of TNBC cells via MEK1/2.

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Data availability

All the data generated or analyzed during the study are included in this article or are available upon request.

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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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Authors and Affiliations

  1. Department of Thyroid and Breast Surgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei Province, 430030, China

    Shiyang Liu, Yao Tian, Chenguang Liu, Zhengwei Gui, Tianyao Yu & Lin Zhang

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Contributions

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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Correspondence to Lin Zhang.

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The authors declare no competing interests.

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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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