Dehydropeptidase 1 promotes metastasis through regulation of E-cadherin expression in colon cancer
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Sang Yoon Park1,8, Seon-Jin Lee1,2, Hee Jun Cho1, Tae Woo Kim1,2, Jong-Tae Kim1, Jae Wha Kim3, Chul-Ho Lee4, Bo-Yeon Kim5, Young Il Yeom6, Jong-Seok Lim7, Younghee Lee8, Hee Gu Lee1,2
1Genome Structure Research Center, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea
2Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Korea
3Biomedical Translational Research Center, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea
4Animal Resource Center, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea
5World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Korea
6Department of Functional Genomics, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea
7Department of Biological Sciences, and The Research Center for Women’s Diseases, Sookmyung Women’s University, Seoul, Korea
8Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Korea
Hee Gu Lee, e-mail: firstname.lastname@example.org
Younghee Lee, e-mail: email@example.com
Keywords: colon cancer, invasion, metastasis, E-cadherin, dehydropeptidase 1
Received: October 20, 2015 Accepted: January 19, 2016 Published: January 27, 2016
Dehydropeptidase 1 (DPEP1) is a zinc-dependent metalloproteinase that is expressed aberrantly in several cancers. The role of DPEP1 in cancer remain controversial. In this study, we demonstrate that DPEP1 functions as a positive regulator for colon cancer cell metastasis. The expression of DPEP1 mRNA and proteins were upregulated in colon cancer tissues compared to normal mucosa. Gain-of-function and loss-of-function approaches were used to examine the malignant phenotype of DPEP1-expressing or DPEP1-depleted cells. DPEP1 expression caused a significant increase in colon cancer cell adhesion and invasion in vitro, and metastasis in vivo. In contrast, DPEP1 depletion induced opposite effects. Furthermore, cilastatin, a DPEP1 inhibitor, suppressed the invasion and metastasis of DPEP1-expressing cells. DPEP1 inhibited the leukotriene D4 signaling pathway and increased the expression of E-cadherin. We also show that DPEP1 mediates TGF-β-induced EMT. TGF-β transcriptionally repressed DPEP1 expression. TGF-β treatment decreased E-cadherin expression and promoted cell invasion in DPEP1-expressing colon cancer cell lines, whereas it did not affect these parameters in DPEP1-depleted cell lines. These results suggest that DPEP1 promotes cancer metastasis by regulating E-cadherin plasticity and that it might be a potential therapeutic target for preventing the progression of colon cancer.
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