Abstract
Abstract PRSS8 is a serine protease and has important physiological and pathophysiological functions, but its roles in cancer initiation and progression are unclear. In this study, a conditional knockout mouse model of Prss8 fl/fl,p-Villin-Cre+ mice were developed and thoroughly characterized at the ages of 3, 6 and 9 months. Intestinal epithelial cell proliferation, migration, and differentiation, were determined. The approaches of gain- and loss of expression of PRSS8 in human colon cancer cells were performed to evaluate anti-cancer and anti-metastasis in vitro and in nude mice by mouse subcutaneous injection, tail vein injection and intra-spleen transplantation. Gene profile and gene set enrichment analysis and mechanistic studies were conducted in vitro and in human colorectal cancer tissues. Results: Genetic deficiency of the Prss8 gene caused spontaneous formation of colitis and inflamed rectum at the early age, but caused intestinal tumors and lymph node metastasis at late age, which was linked to increased intestinal cell proliferation and migration, but decreased cell differentiation. Increased PRSS8 expression showed inhibition of cancer cell growth and metastasis in nude mice, and inhibited migration, invasion, colony formation and tumor sphere formation in vitro, but reduced expression of PRSS8 facilitated malignancies. Mechanistic studies revealed that PRSS8 targets Wnt/β-catenin, epithelial-mesenchymal-transition, and stem cell signaling pathways, which was supported by the results from the Cancer Genome Atlas, and were validated in human colorectal cancers. Conclusion: PRSS8 is a novel tumor suppressor that plays critical roles in the suppression of carcinogenesis and metastasis via targeting Wnt/β-catenin, EMT and stem cell signaling pathway. Citation Format: Yonghua Bao, Yongchen Guo, Yiqiong Yang, Xiaonan Wei, Xiangdong Zhu, Wei Zhang, Wancai Yang. Serine protease PRSS8 suppresses colorectal carcinogenesis and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4006.
Published Version
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