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.
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).
