PRSS8 suppresses colorectal carcinogenesis and metastasis

Yonghua Bao; Yongchen Guo; Yiqiong Yang; Xiaonan Wei; Shanshan Zhang; Yongmeng Zhang; Kai Li; Ming Yuan; Dongli Guo; Virgilia Macias; Xiangdong Zhu; Wei Zhang; Wancai Yang

doi:10.1038/s41388-018-0453-3

PRSS8 suppresses colorectal carcinogenesis and metastasis

Yonghua Bao, Yongchen Guo, Yiqiong Yang, Xiaonan Wei, Shanshan Zhang, Yongmeng Zhang, Kai Li, Ming Yuan, Dongli Guo, Virgilia Macias, Xiangdong Zhu, Wei Zhang, Wancai Yang^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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 Prss8^fl/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.

Original language	English (US)
Pages (from-to)	497-517
Number of pages	21
Journal	Oncogene
Volume	38
Issue number	4
DOIs	https://doi.org/10.1038/s41388-018-0453-3
State	Published - Jan 24 2019

Funding

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.

ASJC Scopus subject areas

Genetics
Molecular Biology
Cancer Research

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10.1038/s41388-018-0453-3

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@article{ff941bd4123b498381293b1bc9459bd8,

title = "PRSS8 suppresses colorectal carcinogenesis and metastasis",

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.",

author = "Yonghua Bao and Yongchen Guo and Yiqiong Yang and Xiaonan Wei and Shanshan Zhang and Yongmeng Zhang and Kai Li and Ming Yuan and Dongli Guo and Virgilia Macias and Xiangdong Zhu and Wei Zhang and Wancai Yang",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2018, Springer Nature Limited.",

year = "2019",

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day = "24",

doi = "10.1038/s41388-018-0453-3",

language = "English (US)",

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AU - Bao, Yonghua

AU - Guo, Yongchen

AU - Yang, Yiqiong

AU - Wei, Xiaonan

AU - Zhang, Shanshan

AU - Zhang, Yongmeng

AU - Li, Kai

AU - Yuan, Ming

AU - Guo, Dongli

AU - Macias, Virgilia

AU - Zhu, Xiangdong

AU - Zhang, Wei

AU - Yang, Wancai

N1 - Funding Information: 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. Publisher Copyright: © 2018, Springer Nature Limited.

PY - 2019/1/24

Y1 - 2019/1/24

N2 - 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.

AB - 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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PRSS8 suppresses colorectal carcinogenesis and metastasis

Abstract

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UN SDGs

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