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Non-canonical WNT5A...
Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells
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- Mehdawi, Lubna M. (author)
- Lund University,Lunds universitet,Cellpatologi, Malmö,Forskargrupper vid Lunds universitet,Cell Pathology, Malmö,Lund University Research Groups,Skåne University Hospital
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- Prasad, Chandra Prakash (author)
- Lund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups,Skåne University Hospital
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- Ehrnström, Roy (author)
- Lund University,Lunds universitet,Patologi, Malmö,Forskargrupper vid Lunds universitet,Pathology, Malmö,Lund University Research Groups,Skåne University Hospital
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- Andersson, Tommy (author)
- Lund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups,Skåne University Hospital
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- Sjölander, Anita (author)
- Lund University,Lunds universitet,Cellpatologi, Malmö,Forskargrupper vid Lunds universitet,Cell Pathology, Malmö,Lund University Research Groups,Skåne University Hospital
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(creator_code:org_t)
- 2016-08-01
- 2016
- English 15 s.
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In: Molecular Oncology. - : Wiley. - 1574-7891. ; 10:9, s. 1415-1429
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- 15-PGDH
- Colon cancer
- JNK
- WNT-5A
- β-Catenin
Publication and Content Type
- art (subject category)
- ref (subject category)
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