WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer

Ripka, S; König, Anika; Buchholz, Malte; Wagner, Martin; Sipos, Bence; Klöppel, Günter; Downward, Julian; Gress, Thomas M.; Michl, Patrick

doi:10.1093/carcin/bgl255

Cited by 144 publications

(139 citation statements)

References 39 publications

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“…However, since these fusion genes are limited to certain types of leukaemia, a broad spectrum diagnosis marker and the index of curative effect assessment is needed that can diagnose leukaemia at an early stage reflecting the change required in treatment. Both our research and past reports have showed that there are remarkable differences in Wnt5a expression levels not only between normal and solid tumor tissues (16)(17)(18)(19), but also between normal or non-malignant hematopoietic tissue and most blood malignancies (20)(21)(22)24,28). Loss of expression of Wnt5a may be one of the reasons that hematopoietic cells obtain malignant proliferation ability.…”

Section: Discussionsupporting

confidence: 62%

“…The ROR2 pathways: Wnt5a can bind and activate the ROR2 tyrosine kinase receptor resulting in the activation of the actin-binding protein, filamin A, and the JNK signaling pathway (11,14). This pathway also can stimulate the TAK1-NLK pathway to phosphorylate (11) and inactivate the active ß-catenin transcription complex (12,15 (16)(17)(18)(19), and Wnt5a has been reported to facilitate cell invasion in human metastatic melanoma (20). However, the function of Wnt5a is complicated as recent findings suggested that it may have an anti-oncogenic role.…”

Section: Introductionmentioning

confidence: 99%

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WNT5A expression is regulated by the status of its promoter methylation in leukaemia and can inhibit leukemic cell malignant proliferation

Deng

Li²,

Zhao³

et al. 2011

Oncol Rep

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Abstract. Although down-regulation of WNT5A expression has been reported in some types of leukaemias, the level of WNT5A expression has not been assessed in leukaemia complete remission (CR) cases, the relationship among WNT5A expression level, the status of its promoter methylation, and the curative effect of leukaemia has not been reported, and the effect of WNT5A on cell proliferation has not been assessed. In this study, we analyzed WNT5A expression in various kinds of leukaemia cases, leukaemia CR cases, non-malignant hematopoietic (NMH) cases, as well as in leukemic cell lines and CD34 + cells. The methylation status of the WNT5A promoter and the levels of the Wnt5a protein were also studied. We also investigated the effect of Wnt5a on leukemic cell proliferation. WNT5A expression level was higher in NMH but lower in leukaemia cases compared to that in CR-cases (P<0.01), and was expressed at low level in leukemic cell lines K562, U937 and Jurkat. Wnt5a protein was positive in NMH, CR cases and CD34 + , but negative in leukaemia cases. WNT5A promoter was methylated in leukaemia cases and all leukemic cell lines, but not in NMH and CR cases. WNT5A expression was up-regulated after exposure to the demethylating agent 5-Aza-2'-deoxycytidine (Aza) in the K562, U937, Jurkat leukemic cell lines and in 83.3% (10/12) of CR patients after cure, respectively. The increased Wnt5a protein can inhibit K562 malignant proliferation and arrest cell cycle at the G2/M phase after exposure to Aza. These results indicate that WNT5A expression was restored in complete remission cases due to demethylation, and Wnt5a can inhibit leukaemic cell proliferation. We propose that WNT5A can act as a suppressor factor in leukemogenesis and can be used as a potential marker for curative effect assessment in leukaemia.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

WNT5A expression is regulated by the status of its promoter methylation in leukaemia and can inhibit leukemic cell malignant proliferation

Deng

Li²,

Zhao³

et al. 2011

Oncol Rep

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“…Immunohistochemical analysis on separate series of breast and pancreatic cancers confirmed that p200 CUX1 protein expression was increased in the high histological grade tumours compared with low-grade tumours 13,58 . Interestingly, CUX1 mRNA and protein expression is increased by TGFβ and is required for TGFβ-induced cell migration and invasion 13,43 .…”

Section: Interstitial Fibrosismentioning

confidence: 80%

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

2014

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“…Most cancer-related deaths are due to metastatic spread, highlighting the need for effective anti-metastatic therapeutics. Wnt5a has also been implicated in promoting cell migration in other tumors such as prostate (32), pancreatic (33), gastric (34), and non-small-cell lung cancers (35), suggesting that Box5 could have far wider potential use as an anti-metastatic drug. In a broader context, Wnt5a is also thought to promote chronic inflammatory diseases such as psoriasis and rheumatoid arthritis (36)(37)(38), highlighting further possible applications for Box5.…”

Section: Discussionmentioning

confidence: 99%

A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion

Jenei

Sherwood

Howlin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

129

114

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The influential role of Wnt5a in tumor progression underscores the requirement for developing molecules that can target Wnt5a-mediated cellular responses. In the aggressive skin cancer, melanoma, elevated Wnt5a expression promotes cell motility and drives metastasis. Two approaches can be used to counteract these effects: inhibition of Wnt5a expression or direct blockade of Wnt5a signaling. We have investigated both options in the melanoma cell lines, A2058 and HTB63. Both express Frizzled-5, which has been implicated as the receptor for Wnt5a in melanoma cells. However, only the HTB63 cell line expresses and secretes Wnt5a. In these cells, the cytokine, TGF␤1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGF␤1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGF␤1 was an unsuitable strategy to pursue. We therefore attempted to target Wnt5a signaling directly. Exogenous Wnt5a stimulation of A2058 cells increased adhesion, migration and invasion, all crucial components of tumor metastasis, and the Wnt5a-derived N-butyloxycarbonyl hexapeptide (Met-Asp-Gly-Cys-Glu-Leu; 0.766 kDa) termed Box5, abolished these responses. Box5 also inhibited the basal migration and invasion of Wnt5a-expressing HTB63 melanoma cells. Box5 antagonized the effects of Wnt5a on melanoma cell migration and invasion by directly inhibiting Wnt5a-induced protein kinase C and Ca 2؉ signaling, the latter of which we directly demonstrate to be essential for cell invasion. The Box5 peptide directly inhibits Wnt5a signaling, representing an approach to anti-metastatic therapy for otherwise rapidly progressive melanoma, and for other Wnt5a-stimulated invasive cancers.inhibitory peptide ͉ malignant melanoma ͉ tumor cell invasion W nt ligands comprise a family of 19 human secreted signaling proteins, which coordinate essential processes required for development and maintenance of tissue homeostasis. Misregulation of Wnt signaling can lead to cancer progression (1). The Wnt ligands are secreted glycoproteins that can be divided based on their ability to activate different intracellular signals, in a tissue-dependent manner. One group primarily activates canonical signaling that controls ␤-catenin stability, while the other is loosely described as ␤-catenin-transcriptionally independent (non-canonical Wnt signaling). However, cross-talk between the two signaling networks does exist (2).Wnt5a is in most situations characterized as a non-canonical Wnt ligand that elicits intracellular signals through association with distinct receptors and co-receptors in a cell specific manner. Wnt5a has been shown to stimulate increases in intracellular Ca 2ϩ levels in developmental models (3) and mammalian cell lines, including breast and thyroid cancer cells (4-6), giving rise to the model of a non-canonical Wnt/Ca 2ϩ signaling pathway. Wnt5a-mediated intracellular increases in Ca 2ϩ levels enables the activation of Ca 2ϩ -regulated proteins, such as protein kinase C (PKC) in a context dependent manner, as reviewed recen...

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WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer

Cited by 144 publications

References 39 publications

WNT5A expression is regulated by the status of its promoter methylation in leukaemia and can inhibit leukemic cell malignant proliferation

WNT5A expression is regulated by the status of its promoter methylation in leukaemia and can inhibit leukemic cell malignant proliferation

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion

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