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PRSS8 suppresses colorectal carcinogenesis and metastasis

Oncogene volume 38, pages 497–517 (2019)Cite this article

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A Correction to this article was published on 22 February 2021

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Abstract

The serine protease PRSS8 has shown important physiological and pathological functions, but its roles in cancer initiation and progression are unclear. We developed and dynamically characterized a conditional knockout Prss8fl/fl, p-Villin-Cre+ mouse model. We found that genetic deficiency of the Prss8 gene caused spontaneous colitis and an inflamed rectum at an early age and caused intestinal tumors at a late age, which were linked to increased intestinal cell proliferation and migration but decreased cell differentiation. Increased PRSS8 expression inhibited cancer cell growth and metastasis in nude mice and inhibited cancer cell migration, invasion, colony formation and tumor sphere formation in vitro, but decreased PRSS8 expression facilitated malignancies in vivo and in vitro. Gene profiling on manipulated cancer cells and intestinal epithelial cells of Prss8 mouse models, gene set enrichment analysis and mechanistic studies revealed that PRSS8 targeted the Wnt/β-catenin, epithelial-mesenchymal transition, and stem cell signaling pathways, which were further supported by the results from the TCGA data mining and validated by immunohistochemical staining on colorectal cancer tissue microarrays. In conclusion, PRSS8 is a novel tumor suppressor that plays critical roles in the suppression of colorectal carcinogenesis and metastasis.

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Acknowledgements

This work was supported in part by grants from the National Nature Science Foundation of China (grants 81672750 and 91229115 to WY, grant 81502105 to YB), a grant from the Key Laboratory of Higher Education Institutes of Shandong Province, the Nature Science Foundation of Shandong Province (grant 2016ZRB14436 to YG) and Taishan Scholar Program of Shandong Province, China, a grant from the Innovation Team of Science and Technology, Henan Province, China, the Startup Fund from Jining Medical University (to YB and YG) and Fostering fund from Jining Medical University (to YG). We would like to thank Prof. Weixing Zhao (Xinxiang Medical University, Xinxiang, China), Prof. Renya Zhang (Jining Medical University, Jining, China) and Prof. Anjia Han (Sun Yat-sen University, Guangzhou, China) for assistance with the histopathology analysis of the mouse models, Prof. Alan Diamond (University of Illinois at Chicago, Chicago, USA) for critical discussion, and Springer Nature Author Services for editing this manuscript. We would also like to thank the Research Histology and Tissue Imaging Core (RHTIC) facility at the University of Illinois at Chicago (Chicago, IL) for their technical assistance.

Author contributions:

Study concept and design: WY, YB; acquisition of data: YB, YG, YY, XW, SZ, YZ, KL, MY, SC; analysis and interpretation of the data: WY, YB, YG; technical and material support: DG, XZ; statistical analysis: YG, WZ; study supervision: WY, YB; drafting of the manuscript: WY; funding: WY, YB, YG, WZ. All authors contributed to critical revision of the manuscript and approved the final version.

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Author notes

  1. These authors contributed equally: Yonghua Bao and Yongchen Guo.

Authors and Affiliations

  1. Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, 272067, China

    Yonghua Bao, Yongchen Guo, Yiqiong Yang, Xiaonan Wei, Xiangdong Zhu, Wei Zhang & Wancai Yang

  2. Department of Pathology, Xinxiang Medical University, Xinxiang, 453003, China

    Shanshan Zhang, Yongmeng Zhang, Kai Li & Ming Yuan

  3. Department of Gastrointestinal Surgery, Affiliated Hospital, Jining Medical University, Jining, 272067, China

    Dongli Guo

  4. Department of Pathology, University of Illinois, Chicago, IL, 60612, USA

    Virgilia Macias & Wancai Yang

  5. Department of Emergency Medicine, University of Illinois, Chicago, IL, 60612, USA

    Xiangdong Zhu

  6. Department of Preventive Medicine, Northwestern University, Chicago, IL, 60611, USA

    Wei Zhang

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  1. Yonghua Bao
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Correspondence to Wancai Yang.

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Bao, Y., Guo, Y., Yang, Y. et al. PRSS8 suppresses colorectal carcinogenesis and metastasis. Oncogene 38, 497–517 (2019). https://doi.org/10.1038/s41388-018-0453-3

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