Bao Yonghua, Li Kai, Guo Yongchen, Wang Qian, Li Zexin, Yang Yiqiong, Chen Zhiguo, Wang Jianguo, Zhao Weixing, Zhang Huijuan, Chen Jiwang, Dong Huali, Shen Kui, Diamond Alan M, Yang Wancai
Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
Department of Pathology, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang 453003, China.
Oncotarget. 2016 May 3;7(18):26780-92. doi: 10.18632/oncotarget.8511.
PRSS8 is a membrane-anchored serine protease prostasin and has been shown an association with carcinogenesis. Herein we found that PRSS8 expression was significantly reduced in colorectal adenomas and adenocarcinomas. The decreased PRSS8 was well correlated with clinical stages, poor differentiation and shorter survival time of colorectal cancer. Furthermore, increase of PRSS8 led to the inhibition of colorectal cancer cell proliferation, knockdown of PRSS8 accelerated cell proliferation in vitro, and overexpressing PRSS8 retarded cancer cell growth in nude mice. Mechanistic studies revealed that PRSS8 inhibited Sphk1/S1P/Stat3/Akt signaling pathway, in terms of inverse association between PRSS8 and Sphk1 in human colorectal cancers and in Sphk1-/- mice. In conclusion, PRSS8 acts as a tumor suppressor by inhibiting Sphk1/S1P/Stat3/Akt signaling pathway, and could be used as a biomarker to monitor colorectal carcinogenesis and predict outcomes.
PRSS8是一种膜锚定丝氨酸蛋白酶前列腺素，已被证明与致癌作用有关。在此我们发现，PRSS8在结直肠腺瘤和腺癌中的表达显著降低。PRSS8的降低与结直肠癌的临床分期、低分化以及较短的生存时间密切相关。此外，PRSS8的增加导致结直肠癌细胞增殖受到抑制，PRSS8的敲低在体外加速了细胞增殖，而PRSS8的过表达则抑制了裸鼠体内癌细胞的生长。机制研究表明，在人类结直肠癌以及Sphk1基因敲除小鼠中，PRSS8与Sphk1呈负相关，PRSS8抑制了Sphk1/S1P/Stat3/Akt信号通路。总之，PRSS8通过抑制Sphk1/S1P/Stat3/Akt信号通路发挥肿瘤抑制作用，可作为监测结直肠癌发生和预测预后的生物标志物。
