Dehydropeptidase 1 promotes metastasis through regulation of E-cadherin expression in colon cancer

Oncotarget. 2016 Feb 23;7(8):9501-12. doi: 10.18632/oncotarget.7033.

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.

Keywords: E-cadherin; colon cancer; dehydropeptidase 1; invasion; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD
  • Cadherins / biosynthesis*
  • Cadherins / genetics
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cilastatin / pharmacology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology*
  • Dipeptidases / antagonists & inhibitors
  • Dipeptidases / metabolism*
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / metabolism
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Leukotriene D4 / antagonists & inhibitors
  • Leukotriene D4 / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / secondary*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • RNA Interference
  • RNA, Messenger / biosynthesis
  • RNA, Small Interfering / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transplantation, Heterologous

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • GPI-Linked Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Transforming Growth Factor beta
  • Cilastatin
  • Leukotriene D4
  • Dipeptidases
  • dipeptidase 1