Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, 272067, China.
Department of Pathology, Xinxiang Medical University, Xinxiang, 453003, China.
Oncogene. 2019 Jan;38(4):497-517. doi: 10.1038/s41388-018-0453-3. Epub 2018 Aug 16.
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, 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.
丝氨酸蛋白酶 PRSS8 具有重要的生理和病理功能，但它在癌症发生和发展中的作用尚不清楚。我们开发并动态表征了条件敲除 Prss8、p-Villin-Cre 小鼠模型。我们发现，Prss8 基因的遗传缺失导致自发性结肠炎和年轻时的直肠炎症，并导致晚年的肠道肿瘤，这与肠道细胞增殖和迁移增加但细胞分化减少有关。PRSS8 的表达增加抑制了裸鼠中癌细胞的生长和转移，并抑制了体外癌细胞的迁移、侵袭、集落形成和肿瘤球体形成，而 PRSS8 的表达减少促进了体内和体外的恶性肿瘤。对 Prss8 小鼠模型中操纵的癌细胞和肠上皮细胞进行基因谱分析、基因集富集分析和机制研究表明，PRSS8 靶向 Wnt/β-catenin、上皮-间充质转化和干细胞信号通路，这进一步得到了 TCGA 数据挖掘结果的支持，并通过对结直肠癌组织微阵列的免疫组织化学染色进行了验证。总之，PRSS8 是一种新型的肿瘤抑制因子，在抑制结直肠癌发生和转移中发挥关键作用。
