Abstract 2044: Characterization of a novel tumor suppressor PRSS8 in colorectal cancer

Abstract

Abstract PRSS8, a glycosylphosphatidylinositol-anchored epithelial extracellular membrane serine protease prostasin, is expressed in normal epithelia and is involved in terminal epithelial differentiation. Aberrantly expression of PRSS8 was observed in human prostate, breast and gastric cancers, and the reduction might be linked to promoter hypermethylation in vitro. However, the expression of PRSS8 in colorectal cancer and its significance in colorectal carcinogenesis and progression are largely unknown. In this study, the expression levels of PRSS8 were firstly determined in four human colorectal cancer cell lines and in 47 paired human colorectal cancer tissues (cancers and their adjacent non-cancer tissues) by real-time PCR, Western blotting and immunohistochemistry. We found that PRSS8 was significantly reduced in colorectal cancer tissues, compared to adjacent non-cancer tissues, and was in very low levels in the colorectal cancer cell lines. Interestingly, the reduced PRSS8 was associated with histopathological stages and differentiation: PRSS8 was lower in poor differentiated cancers and was higher in well differentiated cancers. In addition, the expression levels of PRSS8 were also determined in esophageal cancer, prostate cancer, breast cancer, liver cancer and lung cancer using tissue microarray (TMA) by immunohistochemical staining. Consistent with those in colorectal cancer, PRSS8 protein levels were reduced in all the five cancers and the reduction was associated with cancer differentiation. Further analysis revealed that the patients with lower expression of PRSS8 in esophageal cancer were likely to have a shorter survival time. Functional studies by gain- and loss-expression of PRSS8 showed that increased PRSS8 expression inhibited colon cancer cell proliferation, promoted apoptosis, attenuated cell migration and epithelial-mesenchymal transition (EMT). Mechanistic study showed tumor suppression of PRSS8 was linked to Wnt/beta-catenin signaling pathways. Moreover, PRSS8 interacted with Sphk1 to target S1P and affect EMT/metastasis. Lastly, PRSS8 inhibited colorectal cancer cell growth in tumor-bearing mice, and purified PRSS8 protein showed therapeutic effects in vitro and nude mice. Taken together, this study has identified PRSS8 as a tumor suppressor in colorectal cancer and acts as a key regulator in colorectal cancer formation, progression and outcomes. Therefore, PRSS8 could be a useful biomarker for monitoring colorectal carcinogenesis and progression, and also could have a therapeutic potential for cancers. Note: This abstract was not presented at the meeting. Citation Format: Yonghua Bao, Kai Li, Qian Wang, Yongchen Guo, Rongfei Han, Zhiguo Chen, Zexin Li, Jianguo Wang, Weixing Zhao, Wenliang Han, Jiaqi Wang, Huijuan Zhang, Pan He, Wancai Yang. Characterization of a novel tumor suppressor PRSS8 in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2044. doi:10.1158/1538-7445.AM2015-2044