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Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells.
- Source :
-
Molecular oncology [Mol Oncol] 2016 Nov; Vol. 10 (9), pp. 1415-1429. Date of Electronic Publication: 2016 Aug 01. - Publication Year :
- 2016
-
Abstract
- The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme in prostaglandin E <subscript>2</subscript> catabolism and is down-regulated in colorectal cancer (CRC) tissue. Canonical Wnt signaling is frequently elevated in colon cancers and has been shown to down-regulate 15-PGDH expression. Therefore, we have in the current study investigated if the non-canonical ligand WNT5A relates to increased expression of 15-PGDH in colon cancer cells. In the same cohort of patients, we demonstrated a parallel and significant loss of 15-PGDH and WNT5A protein expression in CRC tissues compared with matched normal colon tissues. Furthermore, patients with low 15-PGDH/WNT5A expression in their tumors showed reduced survival compared with patients with high 15-PGDH/WNT5A expression. To investigate if WNT5A signaling directly affects 15-PGDH expression, we performed in vitro analyses of colon cancer cells (HT-29 and Caco-2). Both cell lines, when treated with recombinant WNT5A (rWNT5A) or Foxy-5, a WNT5A-mimicking peptide, responded by increasing their expression of 15-PGDH mRNA and protein. Our investigations showed that rWNT5A and Foxy-5 induced this increased expression of 15-PGDH through reduced β-catenin signaling as well as increased JNK/AP-1 signaling in colon cancer cells. WNT5A signaling also induced increased 15-PGDH expression in a breast cancer cell line both in vitro and in vivo. In agreement, WNT5A signaling also increased the expression of the differentiation markers sucrose-isomaltase and mucin-2 in colon cancer cells. Our results show that WNT5A signaling regulates 15-PGDH expression, thus uncovering a novel mechanism by which WNT5A acts as a tumor suppressor and suggests that increased 15-PGDH expression could be used as an indicator of a positive response to Foxy-5 in patients treated with this WNT5A agonist.<br /> (Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Breast Neoplasms genetics
Breast Neoplasms pathology
Caco-2 Cells
Colonic Neoplasms drug therapy
Colonic Neoplasms pathology
Female
Gene Expression Regulation, Neoplastic
HT29 Cells
Humans
Hydroxyprostaglandin Dehydrogenases metabolism
Kaplan-Meier Estimate
Mice, Nude
Oligopeptides pharmacology
Oligopeptides therapeutic use
Cell Differentiation genetics
Colonic Neoplasms genetics
Hydroxyprostaglandin Dehydrogenases genetics
Signal Transduction
Up-Regulation genetics
Wnt-5a Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 10
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 27522468
- Full Text :
- https://doi.org/10.1016/j.molonc.2016.07.011