Gene Summary

Gene:WNT5A; wingless-type MMTV integration site family, member 5A
Aliases: hWNT5A
Summary:The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene encodes a member of the WNT family that signals through both the canonical and non-canonical WNT pathways. This protein is a ligand for the seven transmembrane receptor frizzled-5 and the tyrosine kinase orphan receptor 2. This protein plays an essential role in regulating developmental pathways during embryogenesis. This protein may also play a role in oncogenesis. Mutations in this gene are the cause of autosomal dominant Robinow syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein Wnt-5a
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
Show (131)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Melanoma
  • Neoplasm Metastasis
  • Gene Expression
  • Colorectal Cancer
  • Messenger RNA
  • Transcription Factors
  • Transfection
  • RNA Interference
  • Stomach Cancer
  • Epigenetics
  • Down-Regulation
  • Cell Movement
  • Lung Cancer
  • Base Sequence
  • Gene Silencing
  • Neoplasm Proteins
  • Breast Cancer
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Cell Differentiation
  • Oligonucleotide Array Sequence Analysis
  • Prostate Cancer
  • Promoter Regions
  • Staging
  • Proto-Oncogene Proteins
  • RHOA
  • Cell Proliferation
  • rho GTP-Binding Proteins
  • Immunohistochemistry
  • siRNA
  • WNT5A protein, human
  • Neoplasm Invasiveness
  • Neoplastic Cell Transformation
  • Epithelial-Mesenchymal Transition
  • Signal Transduction
  • Chromosome 3
  • Western Blotting
  • Wnt4 Protein
  • DNA Methylation
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: WNT5A (cancer-related)

Gujral TS, Chan M, Peshkin L, et al.
A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis.
Cell. 2014; 159(4):844-56 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
Wnt signaling plays a critical role in embryonic development, and genetic aberrations in this network have been broadly implicated in colorectal cancer. We find that the Wnt receptor Frizzled2 (Fzd2) and its ligands Wnt5a/b are elevated in metastatic liver, lung, colon, and breast cancer cell lines and in high-grade tumors and that their expression correlates with markers of epithelial-mesenchymal transition (EMT). Pharmacologic and genetic perturbations reveal that Fzd2 drives EMT and cell migration through a previously unrecognized, noncanonical pathway that includes Fyn and Stat3. A gene signature regulated by this pathway predicts metastasis and overall survival in patients. We have developed an antibody to Fzd2 that reduces cell migration and invasion and inhibits tumor growth and metastasis in xenografts. We propose that targeting this pathway could provide benefit for patients with tumors expressing high levels of Fzd2 and Wnt5a/b.

Vasiljević N, Ahmad AS, Carter PD, et al.
DNA methylation of PITX2 predicts poor survival in men with prostate cancer.
Biomark Med. 2014; 8(9):1143-50 [PubMed] Related Publications
AIM: We investigated if methylation of candidate genes can be useful for predicting prostate cancer (PCa) specific death.
PATIENTS & METHODS: Methylation of PITX2, WNT5a, SPARC, EPB41L3 and TPM4 was investigated in a 1:2 case-control cohort comprising 45 men with cancer of Gleason score ≤ 7 who died (cases), and 90 men who were alive or died of other causes with survival time longer than the cases (controls). A univariate conditional logistic regression model was fitted by maximizing the likelihood of DNA methylation of each gene versus the primary end point.
RESULTS: A 10% increase in methylation of PITX2 was associated with PCa related death with OR 1.56 (95% CI: 1.17-2.08; p = 0.005).
CONCLUSION: Our study strengthens prior findings that PITX2 methylation is useful as a biomarker of poor outcome of PCa and in addition we also suggest that it may be particularly useful in men with low Gleason score.

Golovastova MO, Bazhin AV, Philippov PP
Cancer-retina antigens -- a new group of tumor antigens.
Biochemistry (Mosc). 2014; 79(8):733-9 [PubMed] Related Publications
Some photoreceptor proteins normally specific for the eye retina are aberrantly expressed in malignant tumors. These proteins include recoverin, visual rhodopsin, transducin, cGMP-phosphodiesterase 6 (PDE 6), cGMP-dependent cationic channels, guanylyl cyclase 1, rhodopsin kinase, and arrestin. By analogy with cancer-testis antigens, these photoreceptor proteins form the group of cancer-retina antigens. It is shown that an aberrant demethylation of the promoter region of recoverin is involved in the aberrant expression of this protein. The cascade Wnt5a → Frizzled-2 → transducin → PDE 6 is shown to function in skin melanoma cells, and this suggests that these cancer-retina antigens can play a functional role. The events accompanying the signal transduction in this cascade, including those involving calcium ions and cGMP-dependent protein kinase (protein kinase G), are discussed.

Wei W, Sun HH, Li N, et al.
WNT5A modulates cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells.
Hepatobiliary Pancreat Dis Int. 2014; 13(5):529-38 [PubMed] Related Publications
BACKGROUND: Although there are many studies on the mechanism of chemoresistance in cancers, studies on the relations between WNT5A and chemoresistance in pancreatic cancer are rare. The present study was to examine the role of WNT5A in the regulation of cell cycle progression and in chemo-resistance in pancreatic cancer tissues and cell lines.
METHODS: Fresh pancreatic cancer and paracarcinoma tissues were obtained from 32 patients. The expressions of WNT5A, AKT/p-AKT and Cyclin D1 were detected by immunohistochemistry, and the correlation between WNT5A expression and clinicopathological characteristics was analyzed. The relationship between WNT5A expression and gemcitabine resistance was studied in PANC-1 and MIAPaCa2 cell lines. The effect of WNT5A on the regulation of cell cycle and gemcitabine cytotoxicity were investigated. The associations among the expressions of p-AKT, Cyclin D1 and WNT5A were also analyzed in cell lines and the effect of WNT5A on restriction-point (R-point) progression was evaluated.
RESULTS: WNT5A, p-AKT and Cyclin D1 were highly expressed in pancreatic cancer tissues, and the WNT5A expression was correlated with the TNM stages. In vitro, WNT5A expression was associated with gemcitabine chemoresistance. The percentage of cells was increased in G0/G1 phase and decreased in S phase after knockdown of WNT5A in PANC-1. WNT5A promoted Cyclin D1 expression through phosphorylation of AKT which consequently enhanced G1-S transition and gemcitabine resistance. Furthermore, WNT5A enhanced the cell cycle progression toward R-point through regulation of retinoblastoma protein (pRb) and pRb-E2F complex formation.
CONCLUSIONS: WNT5A induced chemoresistance by regulation of G1-S transition in pancreatic cancer cells. WNT5A might serve as a predictor of gemcitabine response and as a potential target for tumor chemotherapy.

Zhao Y, Zhang C, Huang Y, et al.
Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-κB signaling in the granulosa cells of PCOS patients.
J Clin Endocrinol Metab. 2015; 100(1):201-11 [PubMed] Related Publications
CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied by chronic low-grade inflammation, but the molecular mechanism remains unclear.
OBJECTIVE: We investigated the action of WNT5a in the development of chronic inflammation in PCOS and the related molecular signaling pathways.
DESIGN AND SETTING: This was a prospective study conducted at the Division of Reproduction Center, Peking University Third Hospital.
PATIENTS: A total of 35 PCOS patients and 87 control women who reported to the clinic for the in vitro procedure and the cause of marital infertility was male azoospermia were included.
MAIN OUTCOME MEASURES: Mural granulosa cells (GCs) of 35 PCOS patients and 37 controls were collected during oocyte retrieval and gene expression was analyzed. The human KGN cells and mural GCs from 50 control subjects (six to eight samples were pooled together for each experiment) were cultured in vitro. The regulation of inflammation and oxidative stress was confirmed by quantitative PCR, flow-cytometric assay, and dual-luciferase reporter assay after inflammatory stimuli or WNT5a overexpression. Relevant signaling pathways were identified using specific inhibitors.
RESULTS: Our data demonstrate significantly elevated WNT5a expression in the mural GCs of PCOS patients compared with the controls. Lipopolysaccharide stimulation increased WNT5a expression in KGN cells and mural GCs, and BAY-117082 and pyrrolidinedithiocarbamic acid [nuclear factor-κB (NF-κB) inhibitor] treatments suppressed WNT5a mRNA below the control level. WNT5a overexpression also enhanced the expression of inflammation-related genes and increased intracellular reactive oxygen species, whereas both BAY-117082 and LY-294002 (phosphatidylinositol 3-kinase inhibitor) significantly inhibited WNT5a-induced inflammation and oxidative stress.
CONCLUSIONS: WNT5a acts as a proinflammatory factor in human ovarian GCs. The up-regulated expression of WNT5a in PCOS increases inflammation and oxidative stress predominantly via the phosphatidylinositol 3-kinase/AKT/NF-κB signaling pathway. The proinflammatory cytokines induced might further enhance WNT5a expression via NF-κB-dependent regulation, indicating a novel regulatory system for chronic inflammation in PCOS.

Samaei NM, Yazdani Y, Alizadeh-Navaei R, et al.
Promoter methylation analysis of WNT/β-catenin pathway regulators and its association with expression of DNMT1 enzyme in colorectal cancer.
J Biomed Sci. 2014; 21:73 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
BACKGROUND: Aberrant DNA methylation as the most important reason making epigenetic silencing of genes is a main mechanism of gene inactivation in patients with colorectal cancer. In this study, we decided to identify promoter methylation status of ten genes encoding WNT negative regulators, and measure the expression of DNMT1 enzyme in colorectal cancer samples.
RESULTS: Aberrant methylation of APC gene was statistically significant associated with age over 50 (p = 0.017), DDK3 with male (p < 0.0001), SFRP4, WIF1, and WNT5a with increasing tumor stage (p = 0.004, p = 0.029, and p = 0.004), SFRP4 and WIF1 with tumor differentiation (p = 0.009 and p = 0.031) and SFRP2 and SFRP5 with histological type (p = 0.001 and p = 0.025). The increasing number of methylated genes correlated with the expression levels of the DNMT1 mRNA.
CONCLUSIONS: The rate of gene promoter methylation of WNT pathway regulators is high in colorectal cancer cells. Hyper-methylation is associated with increased expression of the DNMT1 enzyme.

Zhu HH, Zhu XY, Zhou MH, et al.
Effect of WNT5A on epithelial-mesenchymal transition and its correlation with tumor invasion and metastasis in nasopharyngeal carcinoma.
Asian Pac J Trop Med. 2014; 7(6):488-91 [PubMed] Related Publications
OBJECTIVE: To investigate the correlation between nasopharyngeal carcinoma cell WNT5A and epithelial-mesenchymal transition (emt)/metastasis, and investigate its possible mechanisms.
METHODS: RT-PCR and gene transfection were used to detect the expression of nasopharyngeal carcinoma cell strains WNT5A and EMT related factor 5-8F. Transient transfection of NPC cell line 5-8F was determined by liposome of plasmid with WNT5A gene. The differential expressions of WNT5A and EMT-related factors in cells before and after transfection were detected by RT-PCR. Cell scratch assay and Transwell assay were used to detect the motility abilities of cells before and after 5-8F transfection.
RESULTS: The expressions of WNT5A and EMT related factors matrix metalloproteinase-2 of the WNT5A transferred group in the nasopharyngeal carcinoma cell line 5-8F were higher than the blank control group and the empty vector transferred group, and the transfer ability of the WNT5A transferred group was higher than that in the blank control group and the empty vector transferred group, while the expressions of EMT related factors E-cadherin were lower than that in the blank control group and the empty vector transferred group, and the transfer ability of the WNT5A transferred group was higher than that in the blank control group and the empty vector transferred group.
CONCLUSIONS: In nasopharyngeal carcinoma cells, WNT5A can regulate the epithelial-mesenchymal transition and affect the ability of tumor invasion and metastasis of nasopharyngeal carcinoma.

Li P, Cao Y, Li Y, et al.
Expression of Wnt-5a and β-catenin in primary hepatocellular carcinoma.
Int J Clin Exp Pathol. 2014; 7(6):3190-5 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
It has been reported that changes in Wnt5a expression are closely related to hepatocellular carcinoma (HCC) development, while decreased or abnormal β-catenin expression may promote the invasion and metastasis of tumor cells. In this study, the roles and clinical significance of Wnt-5a and β-catenin expression were analyzed in primary HCC. Real-time PCR (RT-PCR) analysis of Wnt-5a mRNA expression was performed in 26 fresh HCC samples and the corresponding para-carcinoma tissues. Wnt-5a and β-catenin protein expression was detected by immunohistochemical staining of paraffin-embedded tissues of 85 cases of HCC and corresponding para-carcinoma tissues and 15 cases of hepatic cirrhosis. Results showed that Wnt-5a mRNA levels were significantly higher in HCC tissue than in the para-carcinoma tissue (0.102 ± 0.159 and 0.020 ± 0.022, respectively; P < 0.05), while Wnt-5a protein was absent or low in HCC. Wnt-5a expression was detected in significantly fewer HCC tissue samples than in the para-carcinoma and hepatic cirrhosis tissue samples (21.2% (18/85), 81.26% (69/85) and 86.7% (13/15), respectively; P < 0.01). Abnormal localization of β-catenin protein shown by intracytoplasmic or intranuclear staining was observed in 72.94% (62/85) of HCC samples. These observations indicate that the role of Wnt-5a in HCC is mediated at the protein level rather than the transcriptional level. Furthermore, the abnormal localization of β-catenin observed in HCC tissues may be associated with gene mutation leading to the generation of truncated β-catenin proteins, which in turn, may represent an initiating or contributing factor in the development of HCC.

Yao L, Sun B, Zhao X, et al.
Overexpression of Wnt5a promotes angiogenesis in NSCLC.
Biomed Res Int. 2014; 2014:832562 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
To evaluate Wnt5a expression and its role in angiogenesis of non-small-cell lung cancer (NSCLC), immunohistochemistry and CD31/PAS double staining were performed to examine the Wnt5a expression and we analyze the relationships between Wnt5a and microvessel density (MVD), vasculogenic mimicry (VM), and some related proteins. About 61.95% of cases of 205 NSCLC specimens exhibited high expression of Wnt5a. Wnt5a expression level was upregulated in the majority of NSCLC tissues, especially in squamous cell carcinoma, while its expression level in adenocarcinoma was the lowest. Wnt5a was also found more frequently expressed in male patients than in female patients. Except for histological classification and gender, little association was found between Wnt5a and clinicopathological features. Moreover, Wnt5a was significantly correlated with prognosis. Overall, Wnt5a-positive expression in patients with NSCLC indicated shorter survival time. As for vascularization in NSCLC, Wnt5a showed close association with VM and MVD. In addition, Wnt5a was positively related with β -catenin-nu, VE-cadherin, MMP2, and MMP9. The results demonstrated that overexpression of Wnt5a may play an important role in NSCLC angiogenesis and it may function via canonical Wnt signal pathway. This study will provide evidence for further research on NSCLC and also will provide new possible target for NSCLC diagnosis and therapeutic strategies.

Li S, Wang W, Zhang N, et al.
IL-1β mediates MCP-1 induction by Wnt5a in gastric cancer cells.
BMC Cancer. 2014; 14:480 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
BACKGROUND: Both Wnt5a overexpression and macrophage infiltration have been implicated in inflammation and cancer. The aim of this study is to reveal the involvement of Wnt5a in macrophage recruitment in gastric cancer.
METHODS: mRNA expression in gastric cancer tissues and cells was investigated by real-time PCR. Protein secretion by gastric cancer cells was determined by ELISA. PcDNA3.1-Wnt5a expression vector and Wnt5a siRNA vector were used to overexpress and silence Wnt5a expression in gastric cells, respectively. Macrophage migration was analyzed by transwell, and macrophage cytoskeleton was stained with FITC-phalloidin.
RESULTS: Wnt5a was overexpressed in gastric cancer tissues, and correlated with monocyte chemotactic protein 1 (MCP-1) and interleukin 1β (IL-1β), respectively. In gastric cancer cells, Wnt5a induced MCP-1 expression, which was mediated by IL-1β. Conditioned medium from gastric cancer cells transfected with Wnt5a stimulated macrophage chemotaxis and cytoskeletal changes via MCP-1, which were suppressed by recombinant IL-1 receptor antagonist (rIL-1Ra).
CONCLUSIONS: These results suggest that Wnt5a is involved in macrophage recruitment by upregulating MCP-1, and IL-1Ra may be used to inhibit macrophage recruitment in gastric cancer.

Zhao S, Ye X, Xiao L, et al.
MiR-26a inhibits prostate cancer progression by repression of Wnt5a.
Tumour Biol. 2014; 35(10):9725-33 [PubMed] Related Publications
MicroRNAs (miRNAs) are small noncoding RNAs that are involved in different biological processes by suppressing target gene expression. miRNA microarray analysis revealed a significant decrease of miR-26a in prostate cancer tissues versus their normal counterparts, but the role of miR-26a is needed to investigate. In the present study, we found that miR-26a expression was lower in prostate cancer tissues compared with their normal controls, so did the prostate cancer cells. Next, by lentivirus-mediated gain-of-function studies, it was showed that stable miR-26a inhibited cell proliferation, metastasis, and epithelial mesenchymal transition and induced G1 phase arrest in prostate cancer. It was predicted that Wnt5a was a potential target gene of miR-26a by bioinformatics analysis. Then, luciferase assay and Western blot analysis identified that Wnt5a was a new direct target gene of miR-26a and miR-26a inhibited prostate cancer progression via Wnt5a. Altogether, the findings suggested that miR-26a may function as a tumor suppressor in prostate cancer by targeting Wnt5a.

Tiong KL, Chang KC, Yeh KT, et al.
CSNK1E/CTNNB1 are synthetic lethal to TP53 in colorectal cancer and are markers for prognosis.
Neoplasia. 2014; 16(5):441-50 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
Two genes are called synthetic lethal (SL) if their simultaneous mutations lead to cell death, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells specifically, but leave normal cells intact. We present an integrated approach to uncovering SL pairs in colorectal cancer (CRC). Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues, we first identified potential functionally relevant (simultaneously differentially expressed) gene pairs. From the top-ranked pairs, ~20 genes were chosen for immunohistochemistry (IHC) staining in 171 CRC patients. To find novel SL pairs, all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features, e.g. overall survival. Of the 11 predicted SL pairs, MSH2-POLB and CSNK1E-MYC were consistent with literature, and we validated the top two pairs, CSNK1E-TP53 and CTNNB1-TP53 using RNAi knockdown and small molecule inhibitors of CSNK1E in isogenic HCT-116 and RKO cells. Furthermore, synthetic lethality of CSNK1E and TP53 was verified in mouse model. Importantly, multivariate analysis revealed that CSNK1E-P53, CTNNB1-P53, MSH2-RB1, and BRCA1-WNT5A were independent prognosis markers from stage, with CSNK1E-P53 applicable to early-stage and the remaining three throughout all stages. Our findings suggest that CSNK1E is a promising target for TP53-mutant CRC patients which constitute ~40% to 50% of patients, while to date safety regarding inhibition of TP53 is controversial. Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics, and it is readily accessible and applicable to other cancers.

Abdelmaksoud-Dammak R, Miladi-Abdennadher I, Saadallah-Kallel A, et al.
Downregulation of WIF-1 and Wnt5a in patients with colorectal carcinoma: clinical significance.
Tumour Biol. 2014; 35(8):7975-82 [PubMed] Related Publications
Activation of the wingless-type (Wnt) signaling pathway is common in various human cancers including colorectal cancer (CRC). Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind Wnt ligands and therefore inhibits the Wnt signaling pathway. In this study, we aimed to analyze the expression of two members of Wnt signaling (WIF-1 and Wnt5a) in Tunisian patients with sporadic CRC. WIF-1 was frequently methylated in tumor tissues (87.95 %) compared to normal mucosa (39.54 %) and correlated with distant metastasis and vascular invasion (P = 0.001 and 0.037, respectively). The unmethylated profile of the WIF-1 promoter conferred a benefit to patients in terms of overall survival (P log rank = 0.024). In addition, in the group of patients with methylated WIF-1 promoter, the overall survival rate was significantly prolonged for those with small tumor size (<5 cm) and absence of distant metastasis (P log rank = 0.007 and 0.036, respectively). Aberrant CpG methylation of the WIF-1 promoter leads to transcriptional silencing of this tumor suppressor gene in tumor tissues (P = 0.001). Furthermore, we showed that the level of Wnt5a mRNA was significantly lower in tumor compared to normal tissues (P = 0.031) and lower still in those showing more aggressive behavior (presence of lymph nodes and advanced TNM stage). Our finding supports that WIF-1 is frequently methylated and that Wnt5a acts as a tumor suppressor gene in CRC. Loss of WIF-1 and Wnt5a functions results in more aggressive behavior of the disease.

Wang Y, Xia H, Zhuang Z, et al.
Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer.
Cell Death Dis. 2014; 5:e1227 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
The involvement of Axl kinase in non-small cell lung cancer's (NSCLC) acquired resistance to tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has been identified recently, but the mechanism by which Axl contributes to TKI resistance is largely unknown. MicroRNAs (miRNAs) repress gene expression and their critical role in tumorigenesis has been implicated. To investigate the role of miRNAs in the Axl-mediated acquired gefitinib resistance, we examined the Axl-mediated miRNA changes in gefitinib-resistant lung cancers. A panel of Axl kinase-altered miRNAs was identified. In this study, we validate and report that miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future.

Ekström EJ, Bergenfelz C, von Bülow V, et al.
WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells.
Mol Cancer. 2014; 13:88 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
BACKGROUND: Wnt proteins are important for developmental processes and certain diseases. WNT5A is a non-canonical Wnt protein that previously has been shown to play a role in the progression of malignant melanoma. High expression of WNT5A in melanoma tumors correlates to formation of distant metastasis and poor prognosis. This has partly been described by the findings that WNT5A expression in melanoma cell lines increases migration and invasion.
METHODS: Malignant melanoma cell lines were treated with rWNT5A or WNT5A siRNA, and mRNA versus protein levels of soluble mediators were measured using RT-PCR, cytokine bead array and ELISA. The induced signaling pathways were analyzed using inhibitors, Rho-GTPase pull down assays and western blot. Ultracentrifugation and electron microscopy was used to analyze microvesicles. Gene expression microarray data obtained from primary malignant melanomas was used to verify our data.
RESULTS: We show that WNT5A signaling induces a Ca2+-dependent release of exosomes containing the immunomodulatory and pro-angiogenic proteins IL-6, VEGF and MMP2 in melanoma cells. The process was independent of the transcriptional machinery and depletion of WNT5A reduced the levels of the exosome-derived proteins. The WNT5A induced exosomal secretion was neither affected by Tetanus toxin nor Brefeldin A, but was blocked by the calcium chelator Bapta, inhibited by a dominant negative version of the small Rho-GTPase Cdc42 and was accompanied by cytoskeletal reorganization. Co-cultures of melanoma/endothelial cells showed that depletion of WNT5A in melanoma cells decreased endothelial cell branching, while stimulation of endothelial cells with isolated rWNT5A-induced melanoma exosomes increased endothelial cell branching in vitro. Finally, gene expression data analysis of primary malignant melanomas revealed a correlation between WNT5A expression and the angiogenesis marker ESAM.
CONCLUSIONS: These data indicate that WNT5A has a broader function on tumor progression and metastatic spread than previously known; by inducing exosome-release of immunomodulatory and pro-angiogenic factors that enhance the immunosuppressive and angiogenic capacity of the tumors thus rendering them more aggressive and more prone to metastasize.

Ma MZ, Zhuang C, Yang XM, et al.
CTHRC1 acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling.
Neoplasia. 2014; 16(3):265-78, 278.e1-13 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1) in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis.

Mermejo LM, Leal LF, Colli LM, et al.
Altered expression of noncanonical Wnt pathway genes in paediatric and adult adrenocortical tumours.
Clin Endocrinol (Oxf). 2014; 81(4):503-10 [PubMed] Related Publications
CONTEXT: The role of planar cell polarity (Wnt/PCP) and calcium-dependent (Wnt/Ca) noncanonical Wnt pathways in adrenocortical tumours (ACTs) is unknown.
OBJECTIVES: To investigate the gene expression of Wnt/PCP and Wnt/Ca pathways and its association with TP53 p.R337H and CTNNB1 mutations in paediatric and adult ACTs and to correlate these findings with clinical outcome.
PATIENTS: Expression of noncanonical Wnt-related genes was evaluated in 91 ACTs (66 children and 25 adults) by qPCR and the expression of beta-catenin, P53 and protein effectors of Wnt/Ca (NFAT) and Wnt/PCP (JNK) by immunohistochemistry. TP53 and CTNNB1 genes were sequenced.
RESULTS: TP53 p.R337H mutation frequency was higher in children (86% vs 28%), while CTNNB1 mutation was higher in adults (32% vs 6%). Mortality was higher in adults harbouring TP53 p.R337H and in children with CTNNB1 mutations. Overexpression of WNT5A, Wnt/Ca ligand, was observed in children and adults. Overexpression of MAPK8 and underexpression of PRICKLE, Wnt/PCP mediators, were observed in paediatric but not in adult cases. Cytoplasmic/nuclear beta-catenin and P53 accumulation was observed in the majority of paediatric and adult ACTs as well as NFAT and JNK. Overexpression of MAPK8 and underexpression of PRICKLE were associated with mortality in children, while overexpression of WNT5A and underexpression of PRICKLE were associated with mortality in adults.
CONCLUSIONS: In our study, TP53 p.R337H and CTNNB1 mutations correlated with poor prognosis in adults and children, respectively. We demonstrate, for the first time, the activation of Wnt/PCP and Wnt/Ca noncanonical pathway genes, and their association with poor outcome in children and adults, suggesting their putative involvement in ACTs aggressiveness.

Bi L, Liu X, Wang C, et al.
Wnt5a involved in regulation of the biological behavior of hepatocellular carcinoma.
Int J Clin Exp Pathol. 2014; 7(3):987-95 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
OBJECTIVE: Wnt5a has been shown to be involved in cancer progression in a variety of tumor types. Previous experimental studies have indicated that it has been shown to be down-regulated in hepatocellular carcinoma (HCC). The goal of this study was to explore the effect of Wnt5a overexpression in an HCC cell line.
METHODS: We transfected the human HCC cell line Huh7 with a pcDNA3.1-Wnt5a overexpression vector or an empty vector control. The integration of the plasmid DNA and the expression of Wnt5a in Huh7 cells were confirmed by real-time RT-PCR and Western blot. A plate colony formation test was used to calculate the clone formation rate and the cell cycle was analyzed by flow cytometry. The effect of Wnt5a overexpression on cell migration was studied in vitro using a scratch assay and in vivo by xenograft studies in nude mice.
RESULTS: Our results showed that in Huh7 cells with overexpression of Wnt5a, the fraction of cells in the G1 and S phases of the cell cycle was significantly increased compared with untransfected cells. In agreement with this finding, overexpression of Wnt5a was associated with a lower colony formation rate compared with control cells. In our xenograft studies, nude mice injected with Huh7 cells with overexpression of Wnt5a had decreased tumor volumes compared with controls. The vitro scratch assay revealed that Wnt5a overexpression cells had a diminished capacity for cell migration. Furthermore, we studied the expression of important proteins associated with Wnt5a signaling pathway, and it was found that Ror2 and E-cadherin were both increased in Huh7 cells with overexpression of Wnt5a, whereas p53 expression was unaffected.
CONCLUSION: Overexpression of Wnt5a in Huh7 cells was associated with decrease of cell proliferation and migration. Wnt5a may act as a tumor-suppressor gene in HCC, which works through the non-canonical Wnt signaling pathway by binding to the Ror2 and E-cadherin receptor.

Nam S, Chang HR, Kim KT, et al.
PATHOME: an algorithm for accurately detecting differentially expressed subpathways.
Oncogene. 2014; 33(41):4941-51 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
The translation of high-throughput gene expression data into biologically meaningful information remains a bottleneck. We developed a novel computational algorithm, PATHOME, for detecting differentially expressed biological pathways. This algorithm employs straightforward statistical tests to evaluate the significance of differential expression patterns along subpathways. Applying it to gene expression data sets of gastric cancer (GC), we compared its performance with those of other leading programs. Based on a literature-driven reference set, PATHOME showed greater consistency in identifying known cancer-related pathways. For the WNT pathway uniquely identified by PATHOME, we validated its involvement in gastric carcinogenesis through experimental perturbation of both cell lines and animal models. We identified HNF4α-WNT5A regulation in the cross-talk between the AMPK metabolic pathway and the WNT signaling pathway, and further identified WNT5A as a potential therapeutic target for GC. We have demonstrated PATHOME to be a powerful tool, with improved sensitivity for identifying disease-related dysregulated pathways.

Yap LF, Ahmad M, Zabidi MM, et al.
Oncogenic effects of WNT5A in Epstein-Barr virus‑associated nasopharyngeal carcinoma.
Int J Oncol. 2014; 44(5):1774-80 [PubMed] Related Publications
The molecular events that drive the progression of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) are still to be elucidated. Here, we report for the first time the pathogenic significance of an NPC-associated gene, wingless-type MMTV integration site family, member 5A (WNT5A) and the contribution of EBV to its expression. WNT5A is a representative Wnt protein that activates non-canonical Wnt signalling. With regard to its role in carcinogenesis, there is conflicting evidence as to whether WNT5A has a tumour-promoting or tumour-suppressive role. We show that WNT5A is upregulated in primary NPC tissue samples. We also demonstrate that WNT5A expression was dramatically increased in NPC cell lines expressing the EBV-encoded LMP2A gene, suggesting that this EBV-encoded latent gene is responsible for upregulating WNT5A in NPC. In addition, in vitro WNT5A overexpression promotes the proliferation, migration and invasion of NPC cells. Our results not only reveal pro-tumorigenic effects of WNT5A in NPC but also suggest that WNT5A could be an important therapeutic target in patients with EBV-associated disease.

Liu B, Tahk S, Yee KM, et al.
PIAS1 regulates breast tumorigenesis through selective epigenetic gene silencing.
PLoS One. 2014; 9(2):e89464 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
Epigenetic gene silencing by histone modifications and DNA methylation is essential for cancer development. The molecular mechanism that promotes selective epigenetic changes during tumorigenesis is not understood. We report here that the PIAS1 SUMO ligase is involved in the progression of breast tumorigenesis. Elevated PIAS1 expression was observed in breast tumor samples. PIAS1 knockdown in breast cancer cells reduced the subpopulation of tumor-initiating cells, and inhibited breast tumor growth in vivo. PIAS1 acts by delineating histone modifications and DNA methylation to silence the expression of a subset of clinically relevant genes, including breast cancer DNA methylation signature genes such as cyclin D2 and estrogen receptor, and breast tumor suppressor WNT5A. Our studies identify a novel epigenetic mechanism that regulates breast tumorigenesis through selective gene silencing.

Lee MA, Park JH, Rhyu SY, et al.
Wnt3a expression is associated with MMP-9 expression in primary tumor and metastatic site in recurrent or stage IV colorectal cancer.
BMC Cancer. 2014; 14:125 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
BACKGROUND: The wnt/β-catenin signaling pathway is known to affect in cancer oncogenesis and progression by interacting with the tumor microenvironment. However, the roles of wnt3a and wnt5a in colorectal cancer (CRC) have not been thoroughly studied. In the present study, we investigated the expression of wnt protein and the concordance rate in primary tumor and metastatic sites in CRC. To determine the relationship of wnt proteins with invasion related protein, we also analyzed the association between wnt protein expression and the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor receptor-2 (VEGFR-2).
METHODS: Tumor tissue was obtained from eighty-three paraffin- embedded blocks which were using resected tissue from both the primary tumor and metastatic sites for each patient. We performed immunohistochemical staining for wnt3a, wnt5a, β-catenin, MMP-9 and VEGFR-2.
RESULTS: Wnt3a, wnt5a, β-catenin, and MMP-9 expression was high; the proteins were found in over 50% of the primary tumors, but the prevalence was lower in tissue from metastatic sites. The concordance rates between the primary tumor and metastatic site were 76.2% for wnt5a and 79.4% for wnt3a and β-catenin, but VEGFR-2 was expressed in 67.4% of the metastatic sites even when not found in the primary tumor. Wnt3a expression in primary tumors was significantly associated with lymph node involvement (p = 0.038) and MMP-9 expression in the primary tumor (p = 0.0387), mesenchyme adjacent to tumor (p = 0.022) and metastatic site (p = 0.004). There was no other relationship in the expression of these proteins. Vascular invasion in primary tumor tissue may be a potential prognostic marker for liver metastasis, but no significant association was observed among the wnt protein, MMP-9, and VEGFR-2 for peritoneal seeding. In survival analysis, β-catenin expression was significantly correlated with overall survival (p = 0.05).
CONCLUSIONS: Wnt3a and wnt5a expression had a concordance rate higher than 60% with a high concordance rate between the primary tumor and metastatic site. Wnt3a expression is associated with the expression of MMP-9 in primary tumor tissue adjacent mesenchymal tissue, and at the metastatic site. As a prognostic marker, only β-catenin expression showed significant relation with survival outcome.

Shi J, Wang Y, Zeng L, et al.
Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.
Cancer Cell. 2014; 25(2):210-25 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we report a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a "histone H4-mimic" GK-X-GK motif that is diacetylated by Tip60. The diacetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructing an activated Twist/BRD4/P-TEFb/RNA-Pol II complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.

Lee GT, Kang DI, Ha YS, et al.
Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction.
Br J Cancer. 2014; 110(6):1634-44 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
BACKGROUND: Androgen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases.
METHODS: We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model.
RESULTS: In the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2-17.8 months) vs 57 months (95% CI, 19.4-94.6 months)). These results suggest that bone-tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines.
CONCLUSIONS: These observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.

Lock R, Kenific CM, Leidal AM, et al.
Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion.
Cancer Discov. 2014; 4(4):466-79 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
UNLABELLED: The tumor-promoting functions of autophagy are primarily attributed to its ability to promote cancer cell survival. However, emerging evidence suggests that autophagy plays other roles during tumorigenesis. Here, we uncover that autophagy promotes oncogenic RAS-driven invasion. In epithelial cells transformed with oncogenic RAS, depletion of autophagy-related genes suppresses invasion in three-dimensional culture, decreases cell motility, and reduces pulmonary metastases in vivo. Treatment with conditioned media from autophagy-competent cells rescues the invasive capacity of autophagy-deficient cells, indicating that these cells fail to secrete factors required for RAS-driven invasion. Reduced autophagy diminishes the secretion of the promigratory cytokine interleukin-6 (IL-6), which is necessary to restore invasion of autophagy-deficient cells. Moreover, autophagy-deficient cells exhibit reduced levels of matrix metalloproteinase 2 and WNT5A. These results support a previously unrecognized function for autophagy in promoting cancer cell invasion via the coordinate production of multiple secreted factors.
SIGNIFICANCE: Our results delineate a previously unrecognized function for autophagy in facilitating oncogenic RAS-driven invasion. We demonstrate that an intact autophagy pathway is required for the elaboration of multiple secreted factors favoring invasion, including IL-6.

Wang Y, Zheng T
Screening of hub genes and pathways in colorectal cancer with microarray technology.
Pathol Oncol Res. 2014; 20(3):611-8 [PubMed] Related Publications
Here we intend to identify key genes and pathways in the pathogenesis of colorectal cancer (CRC) through analyzing microarray data with bioinformatic tools. The gene expression profile dataset GSE23878 was downloaded from Gene Expression Omnibus and differentially expressed genes (DEGs) were screened out using Student's t-test. GO function and KEGG pathway enrichment analyses were performed for these DEGs with the DAVID online tool. Interaction network was constructed among the over-represented pathways based on the protein-protein interactions within the pathways. Besides, the protein interaction information obtained from HPRD database were applied to constructed protein-protein interaction networks among the DEGs and hub genes and function module were screened out. A total of 2,296 DEGs were obtained and they were enriched in 34 pathways. An interaction network was constructed among 32 pathways, in which p53 signaling pathway acted as the hub pathway as it showed the highest node degree. The protein-protein interaction network comprised 1,481 interaction relationships among 332 genes which included 40 DEGs. Further analysis revealed that theses DEGs formed 7 function modules and many genes, such as PDGFRB, MET, FZD2, CCND1, PRKCB, ARHGEF6, JUP, WNT2, WNT5A and WNT11 were key genes in the networks. The DEGs and disturbed biological functions uncovered in present study may play important roles in the development of CRC and can contribute to the understanding on molecular mechanisms of CRC. Further these DEGs we obtained can be acted as potential biomarkers for diagnosis and therapy of CRC.

Cheng R, Sun B, Liu Z, et al.
Wnt5a suppresses colon cancer by inhibiting cell proliferation and epithelial-mesenchymal transition.
J Cell Physiol. 2014; 229(12):1908-17 [PubMed] Related Publications
Colon cancer remains one of the lethal malignancies in the world. Aberrant activation of canonical Wnt/β-catenin signaling pathway has been observed in colon cancer. In contrast, the non-canonical Wnt signaling functions remain obscure. Wnt5a is a representative non-canonical Wnt ligand which has gained extensive attention nowadays. Wnt5a has been shown to play an important role in EMT in prostate cancer and melanoma, but its role in colon cancer is still ambiguous. Here we have evaluated Wnt5a expression in a large cohort of 217 colon cancers by immunohistochemistry and analyzed its correlation with clinicopathologic characteristics. We found that expression of Wnt5a was diminished significantly in majority of primary colon cancers and negatively related with EMT biomarkers. To further enlighten the mechanism which Wnt5a regulates EMT in vitro, we established ectopic Wnt5a expression models. Protein analysis demonstrated that Wnt5a inhibited EMT and antagonized canonical Wnt signaling in colon cancer cells. Overexpression of Wnt5a impaired cell motility and invasion and inhibited cell proliferation by manipulating Bax. Moreover, Wnt5a suppressed the tumor growth in nude mice and impaired tumorigenicity in vivo. Wnt5a also induced intracellular calcium and activated non-canonical Wnt/Ca(2+) signaling in colon cancer. In summary, although Wnt5a was down-regulated in majority of colon cancers, enhanced Wnt5a expression predict preferable outcome in colon cancer patients. Our findings indicate that Wnt5a might act as tumor suppressor by inhibiting cell proliferation and attenuating EMT in colon cancer cells. Wnt5a could be used as a novel prognostic marker and/or therapeutic target for colon cancer in the future.

Psyrri A, Kotoula V, Fountzilas E, et al.
Prognostic significance of the Wnt pathway in squamous cell laryngeal cancer.
Oral Oncol. 2014; 50(4):298-305 [PubMed] Related Publications
OBJECTIVES: We sought to determine the prognostic significance of the Wnt signaling pathway in operable squamous cell carcinoma of the larynx.
MATERIALS AND METHODS: In an annotated cohort of 289 operable laryngeal cancers we evaluated the prognostic impact of E-cadherin, P-cadherin and β-catenin protein expression with immunohistochemistry, as well as the mRNA expression of 7 key effectors of the Wnt pathway including secreted frizzled-related protein 4 (SFRP4), SNAI2 (SLUG) and WNT5A with qPCR (relative quantification [RQ]).
RESULTS: Using median immunoreactive scores as a pre-defined cut-off, patients whose tumors overexpressed both cytoplasmic E-cadherin and β-catenin experienced longer median OS as compared to those whose tumors overexpressed β-catenin only (median OS 124 vs. 72 months, p=0.0301) and patients whose tumors overexpressed both cytoplasmic and membranous E-cadherin experienced longer DFS as compared to those whose tumors overexpressed cytoplasmic E-cadherin only (median 118 vs. 91 months, p=0.0106). Upon hierarchical clustering of SFRP4, SNAI2 and WNT5A RQ values, profiles including co-expression of all 3 genes but also profiles with under-expression of SNAI2 and WNT5A were associated with worse outcome as compared to profiles not related to the Wnt pathway. In multivariate analysis, clustering was an independent predictor for DFS (p=0.0221) and OS (p=0.0077).
CONCLUSION: We identified gene expression profiles and IHC patterns associated with aberrant Wnt signaling conferring aggressive clinical behavior in operable squamous cell carcinoma of the larynx. Prospective validation of these results will determine whether targeting the Wnt pathway merits investigation in this disease.

Takahashi H, Matsubara S, Kuwata T, et al.
Changes in expression of vascular endothelial growth factor D-related genes in placental mesenchymal dysplasia.
J Obstet Gynaecol Res. 2014; 40(4):1145-9 [PubMed] Related Publications
A recent report indicated that vascular endothelial growth factor (VEGF)-D, regulating cell proliferation and/or differentiation, may be associated with the development of placental mesenchymal dysplasia (PMD), a disorder characterized by cell proliferation/differentiation. In PMD placenta, we examined the expression of five cell-proliferation/differentiation-associated genes, namely, Wnt3a, Wnt5a, β-catenin, VEGF-D and Dickkopf-1 (DKK-1). In PMD, expressions of Wnt3a, Wnt5a and β-catenin were decreased, whereas those of VEGF-D and DKK-1 were increased. These abnormal expressions suggest a relationship between these genes and PMD pathogenesis/pathophysiology.

Zhao C, Bu X, Wang W, et al.
GEC-derived SFRP5 inhibits Wnt5a-induced macrophage chemotaxis and activation.
PLoS One. 2014; 9(1):e85058 [PubMed] Article available free on PMC after 06/11/2015 Related Publications
Aberrant macrophage infiltration and activation has been implicated in gastric inflammation and carcinogenesis. Overexpression of Wnt5a and downregulation of SFRP5, a Wnt5a antagonist, were both observed in gastric cancers recently. This study attempted to explore whether Wnt5a/SFRP5 axis was involved in macrophage chemotaxis and activation. It was found that both Wnt5a transfection and recombinant Wnt5a (rWnt5a) treatment upregulated CCL2 expression in macrophages, involving JNK and NFκB signals. Conditioned medium from Wnt5a-treated macrophages promoted macrophage chemotaxis mainly dependent on CCL2. SFRP5 from gastric epithelial cells (GECs) inhibited Wnt5a-induced CCL2 expression and macrophage chemotaxis. In addition, Wnt5a treatment stimulated macrophages to produce inflammatory cytokines and COX-2/PGE2, which was also suppressed by SFRP5 from GECs. These results demonstrate that Wnt5a induces macrophage chemotaxis and activation, which can be blocked by GEC-derived SFRP5, suggesting that Wnt5a overproduction and SFRP5 deficiency in gastric mucosa may together play an important role in gastric inflammation and carcinogenesis.

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