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WNT5A

Marker Alias

Wingless-type MMTV integration site family, member 5A • hWNT5A • Wnt5a, Wnt-5a

Gene Location

3p21-p14

Expression Location

extracellular

Marker Description

WNT5A, a member of the family of WNT proteins, modulates cell fate and cell behavior during vertebrate development. Experiments performed in Xenopus laevis embryos identified human frizzled-5 (hFz5) as the receptor for the Wnt5A ligand and that the Wnt5A/hFz5 signaling mediates axis induction. WNT5A is a probable developmental protein and may be a signaling molecule which affects the development of discrete regions of tissues. WNT5A is likely to signal over only few cell diameters.

Entre Gene Link

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Pathway

WNT5A is a ligand that activates the beta-catenin-independent pathway in Wnt signaling.

Wnt5a signals through the non-canonical Wnt/Ca(2+)pathway to suppress cyclin D1.

Cancer Indication

colon cancer

Cancer Indication Description

Signaling through the WNT pathway is integrally associated with colon carcinogenesis. Researchers designed a study to test the hypothesis that colon cancer is characterised by aberrant expression of specific WNT genes and frizzled receptors (Fzr). Expression of WNT genes was assessed by in situ, antisense RNA hybridisation in paraffin wax embedded samples of normal and malignant human colon tissues with probes specific for the individual WNT genes. Changes in the expression of some ligands and receptors were seen in colon cancer. Differential expression of WNT5A in normal mucosa was noted, with increased expression at the base of the crypts compared with the luminal villi and slightly increased expression in colon cancer. Data indicate that the expression of members of the WNT signal transduction pathway, distinct from APC and beta-catenin, is integrally associated with the process of colon carcinogenesis. WNT5A may be involved in the progression from normal mucosa to cancer and the expression of Fz1/2 receptors may be involved in processes associated with tumor invasion (Holcombe R etal, Mol Pathol Aug 2002;55(4):220-6).

Cancer Indication

melanoma, malignant

Cancer Indication Description

When melanoma cells were transfected with vectors constitutively overexpressing WNT5A, consistent changes included actin reorganization and increased cell adhesion. No increase in ß-catenin expression or nuclear translocation was observed. An increase in melanoma cell invasion was noted in direct correlation with WNT5A expression and PKC activation. WNT5A expression in human melanoma biopsies directly correlated to increasing tumor grade. therefore, data supports a role for WNT5A in human melanoma progression (Weeraratna A etal, Cancer Cell, Apr 2002;1(3):279-88)

Cancer Indication

gastric cancer

Cancer Indication Description

Researchers have investigated the expression of human WNT5A mRNA in various normal tissues, 66 primary tumors derived from various tissues, and 15 human cancer cell lines. WNT5A mRNA was relatively highly expressed in salivary gland, bladder, uterus, placenta, and fetal kidney. Upregulation of WNT5A mRNA was detected in 5 out of 8 cases of primary gastric cancer, 5 out of 18 cases of primary colorectal tumors, and in 2 out of 7 cases of primary uterus tumors by using matched tumor/normal expression array analysis. Compared with frequent upregulation of WNT5A mRNA in primary gastric cancer, expression levels of WNT5A mRNA in 7 gastric cancer cell lines were significantly lower than that in normal stomach. Frequent upregulation of WNT5A mRNA in human primary gastric cancer might be caused by cancer-stromal interaction (Saitoh T etal, Int J Mol Med May 2002;9(5):515-9).

Cancer Indication

breast cancer

Cancer Indication Description

Loss of two proteins, WNT5A, a G-protein-coupled receptor ligand, or Syk, an intracellular kinase, has in separate studies been associated with poor prognosis in breast cancer patients. Both proteins are involved in cell adhesion, a key event in epithelial cancer metastasis. Syk was studied to find whether it is part of the WNT5A/discoidin domain receptor-1 (DDR1) signaling pathway and if a signaling interaction of these proteins is important for breast cancer-specific survival. The signaling interactions between WNT5A/DDR1 and Syk were investigated in mammary cell lines. Their mRNA and protein levels and the respective clinical correlates were measured in 94 cases of primary breast cancer. The expression of WNT5A and Syk correlated in 4 out of 5 tumor cell lines. However, despite a constitutive association between Syk and the WNT5A-dependent adhesion receptor DDR1, there was no evidence of a WNT5A/DDR1-mediated activation of Syk. Instead, ß integrins initiate the adhesion-induced activation of Syk. In tumors from breast cancer patients, the protein expression of WNT5A and Syk were differently regulated at the translational and transcriptional level, respectively. Analysis of breast cancer-specific survival revealed that the presence of WNT5A and Syk in primary tumors has good predictive value for a favorable outcome. A simultaneous loss of both proteins did not reduce survival more than loss of either. Despite the difference in regulation of WNT5A and Syk protein expression and their lack of signaling interaction, the data indicates that a favorable prognosis in breast cancer requires the expression and signaling activity of both (Dejmek J, etal, Clin Cancer Res, 15 Jan 2005;11(2 Pt 1):520-8).

Cancer Indication

prostate cancer

Cancer Indication Description

According to investigators at Hiroshima University, in Japan, abnormal expression of Wnt5a and beta-catenin was observed in 27 (28%) and 49 (50%) of 98 prostate cancer cases, respectively, by IHC analyses. Simultaneous expression of Wnt5a and beta-catenin was observed in only 5cases, suggesting exclusive expression. Unlike beta-catenin, the positive detection of Wnt5a was correlated with high Gleason scores and biochemical relapse of prostate cancer. Knockdown and overexpression of Wnt5a in human prostate cancer cell lines respectively reduced and stimulated invasion activities, which required Frizzled2 and Ror2 as Wnt receptors. Wnt5a activated Jun-N-terminal kinase through protein kinase D (PKD) and the inhibition of PKD suppressed Wnt5a-dependent cell migration and invasion. In addition, Wnt5a induced the expression of metalloproteinase-1 through the recruitment of JunD to its promoter region. These results suggest that Wnt5a promotes the aggressiveness of prostate cancer and that its expression is involved in relapse after prostatectomy (Yamamoto H, etal, Oncogene, 8 Apr 2010;29(14):2036-46).

Cancer Indication

leukemia

Cancer Indication Description

Deregulation of the non-canonical Wnt/Ca(2+)pathway found in animal models suggests that it acts as tumor suppressor in acute myeloid leukemia (AML). DNA methylation is the main mechanism of regulation of the canonical Wnt pathway in AML. Investigtors at Reina Sofia Hospital, Maimonides Institute for Biomedical Research (Cordoba, Spain) analyzed the methylation status of WNT5A promoter-exon 1 in 11 AML-derived cell lines and 252 patients with AML. WNT5A hypermethylation was noted in 7 cell lines and in 43% (107/252) of patients with AML. WNT5A methylation was associated with decreased WNT5A expression (p<0.001) that was restored after exposure to 5-Aza-2'-deoxycytidine. Moreover, WNT5A hypermethylation correlated with upregulation of Cyclin D1 expression (p<0.001). Relapse (15% versus 37%, p<0.001) and mortality (61% versus 79%, p=0.004) rates were lower for patients in the non-methylated group. Disease-free survival and osl at 6 and 7 years, respectively, were 60% and 27% in patients with unmethylated WNT5A compares to 20% and 0% for patients with methylated WNT5A (p=0.0001 and p=0.04, respectively). Interestingly, significant differences were also observed when the analysis was carried out according to cytogenetic risk groups. These data suggest that WNT5A is a putative tumor suppressor in AML which, when silenced by methylation this epigenetic event is associated with upregulation of Cyclin D1 expression and confers poor prognosis in patients with AML (Martín V, etal, Cancer Sci, Feb 2010;101(2):425-32).

Cancer Indication

lung cancer

Cancer Indication Description

Investigators constructed plasmids containing the WNT5A sense gene and a siRNA eukaryotic expression vector and transfected them into the human lung squamous carcinoma cell line H157 and adenocarcinoma cell line A549. Expression of WNT5A protein significantly stimulated cell proliferation while transfection with siRNA plasmids suppressed Wnt-5 expression and cell proliferation (Huang Y, etal, Oncol Rep Jan 2010;23(1):177-81; liuguoxiang@162.com).

Current as of

August 09, 2010

  

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