Disease relevance of WNT2

• We have also reported frequent up-regulation of WNT2 and WNT5A in primary gastric cancer, which is probably due to cancer-stromal interaction [1].
• WNT2 is a tumor marker of gastric and colorectal cancer [2].
• WNT2 and human gastrointestinal cancer (review) [2].
• WNT2 mRNA is also frequently up-regulated in colorectal polyps, primary colorectal cancer of stage A-C, and also in liver metastasis from colorectal cancer [2].
• Up-regulation of WNT2 mRNA by estrogen might play a key role in some cases of human breast cancer through activation of the beta-catenin - TCF signaling pathway [3].

Psychiatry related information on WNT2

• No association between the WNT2 gene and autistic disorder [4].

High impact information on WNT2

• Important questions that remain unsolved include the identity of the vertebrate IRP that triggers the apoptotic cascade and the identities of the crucial substrates whose cleavage results in the dramatic morphological changes during apoptosis [5].
• Our results identify a regulatory link between energy and iron metabolism in vertebrates and invertebrates, and suggest biological functions for the IRE/IRP regulatory system in addition to the maintenance of iron homeostasis [6].
• Differences in the two binding sites may be important in the function of the IRE-IRP regulatory system [7].
• Recombinations between IRP and cystic fibrosis [8].
• DNA sequences from the IRP locus that recognize RFLPs are proving to be highly informative for prenatal diagnosis [8].

Chemical compound and disease context of WNT2

• WNT2 is up-regulated by beta-estradiol in human MCF-7 cells; however, the mechanism of WNT2 up-regulation in most cases of gastrointestinal cancer remains to be elucidated [2].
• These and additional data stemming from inhibition of heme synthesis with succinylacetone or from iron overload suggest that highly efficient utilization of iron in mitochondrial heme synthesis during normal erythropoiesis alters the regulation of iron metabolism via the IRE/IRP system [9].

Biological context of WNT2

• ST7 is a tumor suppressor gene, which is clustered with WNT2 gene in human chromosome 7q31 region [10].
• WNT2 gene on human chromosome 7q31 is a paralog of the WNT2B gene on human chromosome 1p13 [2].
• WNT2 gene is one of the targets for pharmacogenomics in the field of oncology [2].
• We screened WNT2 for DNA polymorphisms by sequencing all exons and adjacent intronic regions in 24 autistic patients, and identified not only the WNT2 variants reported previously (two common single-nucleotide polymorphisms (SNPs) in the 5' upstream region and the 3' untranslated region (UTR), respectively), but also two new SNPs in its 3' UTR [11].
• Our interpretation of these findings is that it is unlikely that DNA variations in RELN and WNT2 play a significant role in the genetic predisposition to autism [11].

Anatomical context of WNT2

• WNT2 mRNA is expressed in human fetal lung and placenta, but almost undetectable in normal gastrointestinal tract [2].
• Detection of theWNT2 protein in feces by immunohistochemistry or ELISA and WNT2 mRNA in feces by cDNA-PCR or custom-made microarray could be applied for screening of colorectal cancer [2].
• This is the first report on differential regulation of WNT2, WNT2B1, and WNT2B2 mRNAs in human cancer cell lines [3].
• Furthermore, expression analysis demonstrated WNT2 expression in the human thalamus [12].
• WNT2 was up-regulated in 14 out of 18 cases of primary colorectal cancer, 4 out of 7 cases of uterus tumor, 2 out of 9 cases of breast cancer, and in 2 out of 14 cases of kidney tumor [13].

Associations of WNT2 with chemical compounds

• WNT2 is an evolutionarily conserved secreted-type glycoprotein belonging to the WNT family [2].
• WNT2B2, but not WNT2 and WNT2B1, was expressed in MCF-7 cells. beta-estradiol (100 nM) induced a transient up-regulation of WNT2 in MCF-7 cells, and also induced down-regulation of WNT2B2 [3].
• Retinoic acid (10 microM) induced a transient up-regulation of WNT2 in NT2 cells [3].
• We then assessed the antiproliferative effects of the Wnt2 antibody and Alimta, one of the current standard treatments of MPM [14].
• However, despite the far greater Fe chelation efficacy of 311 compared with DFO, a similar increase in IRP-RNA binding activity occurred after 2 to 4 hours of incubation with either chelator, and the binding activity was not inhibited by cycloheximide [15].

Physical interactions of WNT2

• Here, we showed that three potential AS-IREs, i.e. AS-IRE1, 4, and 5, derived from HER-2/neu antisense sequence could bind endogenous iron regulatory protein (IRP) and, when placed in 5' untranslated region (5'UTR) of a reporter gene, the gene expression could be translationally repressed by recombinant IRP in vitro [16].
• Purified human brain IRP protein has a molecular mass of approximately 100 kDa and is capable of forming two RNA-protein complexes with ferritin IRE RNA and reacts strongly with IRP1 antiserum [17].

Other interactions of WNT2

• We genotyped all four WNT2 polymorphisms and a polymorphic trinucleotide repeat in the 5' UTR of RELN in 107 families with multiple autistic children, and evaluated evidence for association between these variants and autism by the transmission disequilibrium test (TDT) [11].
• In conclusion, (1) alterations of key regulators of the Wnt signaling are frequent in the pathogenesis of BE; (2) the APC and SFRP1 genes are inactivated by promoter methylation in BE; (3) the WNT2 gene is upregulated along the progression from low-grade dysplasia to EAC [18].
• Synchronous up-regulation of FZD10 and WNT2 mRNAs might lead to activation of the WNT signaling pathway in human breast cancer [19].
• Our data demonstrate that TNF-alpha may exert its effect by inhibiting IR autophosphorylation in HAEC and also by reducing IR protein (IRP) expression [20].
• Of these four presumably activated oncogenes, two, MYCN and WNT2, were previously not assumed to play a pathogenic role in stomach cancer [21].

Analytical, diagnostic and therapeutic context of WNT2

• Because WNT2 up-regulation leads to carcinogenesis through activation of the WNT-beta-catenin pathway, WNT2 specific antagonist might be applied for chemoprevention or treatment of gastrointestinal cancer [2].
• In a multiple sequence alignment of human, mouse, and Fugu, the putative WNT2 promoter sequence is shown to contain highly conserved elements that may be transcription factor or other regulatory binding sites [22].
• Wnt2 and Wnt5a mRNA was localized by in situ hybridization in 13 cases (three malignant) chosen to reflect the different beta-catenin staining patterns [23].
• Using a gel retardation assay, the observed molecular lesions were shown to variably reduce the IRE affinity for an iron regulatory protein (IRP), which inhibits ferritin mRNA translation [24].
• RNA-bandshift assays showed that in monocytes and macrophages from 16 control subjects, IRP activity was transiently elevated 4 hours after treatment with LPS and IFN-gamma but remarkably downregulated thereafter [25].

References