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Mast cells inhibit colorectal cancer development by inducing ER stress through secreting Cystatin C

Abstract

Mast cells (MCs) are abundantly distributed in the human intestinal mucosa and submucosa. However, their roles and mechanisms in the development of colorectal cancer (CRC) are still unclear. In the present research, we found that the infiltration density of MCs in CRC tissues was positively correlated with improved patients’ prognoses. Moreover, MCs suppressed the growth and induced the apoptosis of CRC cells in vitro and in vivo but had no effect on normal colonic epithelial cells. The present study revealed that MCs specifically induced endoplasmic reticulum stress (ERS) and activated the unfolded protein response (UPR) in CRC cells but not in normal cells, which led to the suppression of CRC development in vivo. Furthermore, we found that the secreted Cystatin C protein was the key factor for the MC-induced ERS in CRC cells. This work is of significance for uncovering the antitumor function of MCs in CRC progression and identifying the potential of CRC to respond to MC-targeted immunotherapy.

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Fig. 1: Infiltration of MCs into CRC tissues predicted improved prognosis.
Fig. 2: CM from MCs induced the growth arrest and apoptosis of CRC cells.
Fig. 3: MCs specifically induced ERS and activated UPR in CRC cells.
Fig. 4: MCs activated ERS and inhibited the growth of CRC cells in vivo.
Fig. 5: MCs inhibited the development of CRC by inducing ERS.
Fig. 6: Cystatin C protein was the key factor of MCs in inducing ERS of CRC cells.
Fig. 7: Knockout of Cystatin C in MCs alleviated their inhibitory effect on CRC development.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We wish to thank Professor Jianfeng Chen from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences for his scientific vision and kindly support during the study conduction.

Funding

This work was financially supported by the National Natural Science Foundation of China (Nos. 82072647, 31741087, 81602262 and 82173190).

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FS and YZ carried out most of the experiments, assembled the figures, and wrote the manuscript. QC assisted with the data analysis and the manuscript revision. DB gave his help for bioinformatic analysis. MY and LL provided suggestions for experimental design. ML, HZ and YL provided suggestions for manuscript writing. QW, HQ and JL designed and supervised the project.

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Correspondence to Qing Wei, Huanlong Qin or Jiyu Li.

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The study protocol was approved by the Ethics Committees of Shanghai Tenth People’s Hospital and Experimental Animal Ethics Committee of Shanghai Tenth People’s Hospital. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

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Song, F., Zhang, Y., Chen, Q. et al. Mast cells inhibit colorectal cancer development by inducing ER stress through secreting Cystatin C. Oncogene 42, 209–223 (2023). https://doi.org/10.1038/s41388-022-02543-z

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