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

Abstract

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

A potential anti-tumor effect of leukotriene C4 through the induction of 15-hydroxyprostaglandin dehydrogenase expression in colon cancer cells

“…We observed significantly lower CysLT 2 staining in the tumor tissue compared with the corresponding normal tissue from the same patient. In a recent study, these paired samples were also stained with a 15-PGDH-specific antibody, and the normal colon samples showed significantly higher 15-PGDH protein expression compared to the matched colon cancer samples [21]. These findings are in good agreement with our mRNA data.…”

Downregulation of 15‐hydroxyprostaglandin dehydrogenase by interleukin‐1β from activated macrophages leads to poor prognosis in pancreatic cancer

“…According to previous studies, HPGD has been reported to be a tumor suppressor gene in several types of cancer. [18][19][20] Here, we showed that 15-PGDH expression in PDAC cells is sup- 21,31,32 In fact, LPS-treated activated macrophages significantly increased CD163 expression.…”

“…Recently, 15-PGDH, which degrades prostaglandin, has attracted attention, and inhibition of 15-PGDH caused PGE 2 accumulation and promoted tissue regeneration in mice by expanding the tissue stem cell fraction. 17 Although 15-PGDH is known to be a tumor suppressor in colon, lung, and breast cancers, [18][19][20] the relationship between 15-PGDH expression and PDAC progression is still unclear. Here, we elucidated the mechanism underlying regulation of 15-PGDH expression and the prognostic impact of 15-PGDH expression in PDAC.…”

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

“…At the same time, it is known that WNT5A acts to suppress tumour formation in several cancer types . In colon cancer, it even induces differentiation of neoplastic cells . A previous study showed that WNT5A is downregulated in Wilms tumour .…”

“…WNT5A is a key effector molecule in nephrogenesis and is also integrated with Hippo signalling [29,35]. It also plays a role in tumorigenesis and has been used to enforce the differentiation of colon cancer cells [36]. WNT5A mRNA expression was higher in IRX5 −/− compared to IRX3 −/− cells ( Figure 5B), while WNT5A protein was expressed in all histological elements of WiT49-derived tumours irrespective of IRX3/5 status ( Figure 6A-F).…”