Tumor suppressor PRSS8 targets Sphk1/S1P/Stat3/Akt signaling in colorectal cancer
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Yonghua Bao1,*, Kai Li2,*, Yongchen Guo1,*, Qian Wang3, Zexin Li4, Yiqiong Yang1, Zhiguo Chen5, Jianguo Wang4, Weixing Zhao2,5, Huijuan Zhang5, Jiwang Chen6, Huali Dong7, Kui Shen7, Alan M. Diamond7, Wancai Yang1,7
1Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China
2Department of Pathology, the First Affiliated Hospital, Xinxiang Medical University, Xinxiang 453003, China
3Department of Immunology, Xinxiang Medical University, Xinxiang 453003, China
4Department of Surgical Oncology, the First Affiliated Hospital, Xinxiang Medical University, Weihui 453003, China
5Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China
6Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
7Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
*These authors have contributed equally to this work
Wancai Yang, email: [email protected]
Keywords: PRSS8, colorectal cancer, tumor suppressor, Sphk1, Stat3
Abbreviations: PRSS8, protease serine 8; Stat3, signal transducer and activator of transcription 3; Sphk1, sphingosine kinase 1; S1PR, Sphingosine-1- Phosphate receptor
Received: December 23, 2015 Accepted: March 06, 2016 Published: March 31, 2016
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.
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