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Mol Oncol. 2016 Nov;10(9):1415-1429. doi: 10.1016/j.molonc.2016.07.011. Epub 2016 Aug 1.

Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells.

Author information

1
Department of Translational Medicine, Division of Cell and Experimental Pathology, Skåne University Hospital Malmö, Lund University, Sweden.
2
Department of Translational Medicine, Division of Pathology, Skåne University Hospital Malmö, Lund University, Sweden.
3
Department of Translational Medicine, Division of Cell and Experimental Pathology, Skåne University Hospital Malmö, Lund University, Sweden. Electronic address: anita.sjolander@med.lu.se.

Abstract

The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme in prostaglandin E2 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.

KEYWORDS:

15-PGDH; Colon cancer; JNK; WNT-5A; β-Catenin

PMID:
27522468
PMCID:
PMC5423213
DOI:
10.1016/j.molonc.2016.07.011
[Indexed for MEDLINE]
Free PMC Article

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