Abstract
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.
Highlights
Colorectal cancer (CRC) is one of the most common neoplastic diseases in industrialized countries and is the fourth most common cause of death from cancer worldwide [1, 2]
By comparing the expression profiles of Dehydropeptidase 1 (DPEP1) mRNA and protein in cancer and noncancerous tissues, and characterizing the role of this gene in regulating invasion and metastasis both in vitro and in vivo, we found that DPEP1 regulates E-cadherin plasticity during TGF-βmediated epithelial to mesenchymal transition (EMT), and promotes malignant progression in colon cancer
We examined the expression levels of DPEP1 mRNA in 27 normal/tumor tissue pairs by quantitative real-time polymerase chain reaction analysis
Summary
Colorectal cancer (CRC) is one of the most common neoplastic diseases in industrialized countries and is the fourth most common cause of death from cancer worldwide [1, 2]. Aggressive metastatic cancers are characterized by their high capacity for migration, and subsequent invasion and adhesion in distant organs [5, 6]. Acquisition of these properties by cancer cells involves aberrant changes in the expression level of several genes. Accumulating evidences have been described that epithelial-mesenchymal plasticity, referring to the reversible processes of the EMT and the mesenchymal to epithelial transition (MET), is involved in metastatic progression [10,11,12]. It has been proposed that a reduction of EMT inducer factors leads to the MET in distant metastatic sites [12]
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