Disease relevance of DKK3

• In order to study direct effects of these proteins on adrenocortical cell function, we created adenoviruses encoding human DKK3 and WNT4 [1].
• Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway [2].
• Our studies thus indicate that loss of DKK-3 expression may contribute to melanoma progression [3].
• Dkk-3/REIC was downregulated in 11 out of the 20 human hepatoma tissues as compared to their counterparts of noncancerous liver tissues by northern blot analysis [4].
• Similarly, the REIC gene expression was decreased in 14 of 24 fresh non-small cell lung cancer specimens (58%) compared to that in corresponding non-cancerous tissue, though allelic loss and tumor-specific mutation were rare [5].
• Our demonstration of the mechanisms underlying REIC/Dkk-3-induced cell death indicates that REIC/Dkk-3 plays a pivotal role in the biology of human malignant glioma and suggests that REIC/Dkk-3 is a promising candidate for molecular target therapy [6].

High impact information on DKK3

• Using cDNA microarray analysis, fibroblasts derived from palmoplantar skin expressed high levels of dickkopf 1 (DKK1; an inhibitor of the canonical Wnt signaling pathway), whereas nonpalmoplantar fibroblasts expressed higher levels of DKK3 [7].
• The expression of DKK3 was accompanied by attenuation of the mitogen-activated protein kinase pathway [8].
• Ectopic expression of SFRP1 or DKK3 resulted in decreased proliferation [8].
• Here, we showed that expression of REIC/Dkk-3 was consistently reduced in human prostate cancer tissues in a stage-dependent manner [9].
• Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase [9].

Biological context of DKK3

• This study indicates a possible role of Dkk3 in regulating bone formation [10].
• For studying the effects of dickkopf homolog 3 (Dkk3) in chondrogenesis and osteogenesis, C3H10T1/2 mesenchymal progenitors were used [10].
• CONCLUSIONS: A bioinformatics analysis enabled the identification of Dkk3 as a pivotal gene with a novel function in endochondral bone formation [10].
• Saos-2 cells, which ectopically express Dkk-3, do not undergo apoptosis and exhibit enhanced resistance to serum starvation and chemotherapy-induced cytotoxicity [2].
• Transfection of Dkk-3 and dominant-negative LRP5 into Saos-2 cells significantly reduces invasion capacity and cell motility [2].

Anatomical context of DKK3

• In situ hybridization on adult human adrenal gland sections showed that DKK3 expression was much higher in the ZG than in the ZF or ZR [11].
• Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex [11].
• Functional assays with stable DKK-3 transfected cell lines revealed that DKK-3 expression increased cell-cell adhesion and decreased cell migration [3].
• Dkk3 was expressed in some samples, with stronger expression in deep gastric glands [12].
• The Wnt family molecules Dickkopf-3 (DKK3) and WNT4 are present at higher concentrations in the zona glomerulosa than in the rest of the adrenal cortex [1].

Associations of DKK3 with chemical compounds

• DKK3 decreased cyclic AMP-stimulated CYP17 [1].
• When added to cultured human adrenocortical cells, DKK3 inhibited aldosterone and cortisol biosynthesis, either alone or together with cyclic AMP [1].
• A notable single nucleotide polymorphism in the coding region (cSNP) with an amino acid substitution of glycine (GGG) to arginine (AGG) was found at codon 335 of the REIC gene [5].

Other interactions of DKK3

• The higher level of DKK3 and WNT4 expression in ZF/ZG cells was confirmed by real-time PCR [11].
• Dickkopf (Dkk) genes comprise an evolutionary conserved small gene family of four members (Dkk1-4) and a unique Dkk3-related gene, Dkkl1 (soggy) [13].
• Dkk3 and Dkk2 expression was also concentrated at crypt bases [12].
• We analysed CpG island methylation of the Dkk-3 promoter in six ALL cell lines and 183 ALL patients [14].
• Injection of an IL-7 antibody partially abrogated the suppressive effect of Ad-REIC-infected NHF [15].

Analytical, diagnostic and therapeutic context of DKK3

• Northern blotting showed higher DKK3 transcript levels in ZF/ZG than ZR samples [11].
• Quantitative RT-PCR confirmed the expression of Dkk3 in the implants [10].
• Western blot analysis and immunohistochemistry revealed a significant decrease in REIC/Dkk-3 protein levels in 6 of the 7 and 13 of the 14 RCCC cases analyzed, respectively [16].
• Consistent with this, depletion of Dkk-3 disrupted acinar morphogenesis of RWPE-1 cells in a three-dimensional cell culture model [17].
• In the present study, we examined the potential utility of REIC/Dkk-3-based gene therapy against human testicular cancer [18].

References