Статті в журналах: "Dickkopf-3 (DKK3)"

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Suwa, T., M. Chen, CL Hawks, and PJ Hornsby. "Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex." Journal of Endocrinology 178, no. 1 (July 1, 2003): 149–58. http://dx.doi.org/10.1677/joe.0.1780149.

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The mechanisms underlying the differentiation of the adrenal cortex into zones are unclear. Microarray studies on RNA from microdissected zona reticularis (ZR) and zona fasciculata/zona glomerulosa (ZF/ZG) derived from adult human adrenal glands showed that a gene of the dickkopf family (DKK), DKK3, is differentially expressed in the zones. The Dickkopf proteins are morphogens involved in Wnt signalling. Northern blotting showed higher DKK3 transcript levels in ZF/ZG than ZR samples. 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. DKK3 expression was also higher in the medulla. We screened for expression of other members of the DKK family and the related Wingless-type mouse mammary tumor virus integration site gene family (WNT), frizzled (FZD), and dishevelled (DVL) gene families. Among dickkopf family members, only DKK3 was expressed at a detectable level in both human and mouse adrenocortical RNA samples. Consistent with previously published data on the effects of Wnt4 gene disruption in the mouse, we found only WNT4 expression within the WNT family in both human and mouse RNA. Northern blotting showed that WNT4 was expressed at a higher level in ZF/ZG cells than in ZR. The higher level of DKK3 and WNT4 expression in ZF/ZG cells was confirmed by real-time PCR. In the frizzled and dishevelled families we found FZD1, FZD2 and DVL3 transcripts in human adrenocortical RNA, and FZD2 and DVL3 in mouse adrenocortical RNA. These data show that a variety of genes of the Wnt signalling pathways are expressed in the adrenal cortex. The zonal distribution of DKK3 expression suggests that it could be involved in zonal differentiation or growth.

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Zewinger, Stephen, Thomas Rauen, Michael Rudnicki, Giuseppina Federico, Martina Wagner, Sarah Triem, Stefan J. Schunk, et al. "Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss." Journal of the American Society of Nephrology 29, no. 11 (October 2, 2018): 2722–33. http://dx.doi.org/10.1681/asn.2018040405.

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BackgroundThe individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia–derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss.MethodsTo investigate urinary DKK3’s potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment.ResultsMedian urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course.ConclusionsUrinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.

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Sciascia, Savino, Alice Barinotti, Massimo Radin, Irene Cecchi, Elisa Menegatti, Edoardo Terzolo, Daniela Rossi, Simone Baldovino, Roberta Fenoglio, and Dario Roccatello. "Dickkopf Homolog 3 (DKK3) as a Prognostic Marker in Lupus Nephritis: A Prospective Monocentric Experience." Journal of Clinical Medicine 11, no. 11 (May 25, 2022): 2977. http://dx.doi.org/10.3390/jcm11112977.

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Background: The gold standard for diagnosis of lupus nephritis (LN) is still represented by renal biopsy, and serological prognostic biomarkers are still lacking. Dickkopf homolog-3 (DKK3) has been suggested as a marker of tissue fibrosis in different conditions; however, its role in autoimmune diseases needs to be elucidated. Here, we investigated the prognostic role of DKK3 in systemic lupus erythematosus (SLE) patients with and without LN, assessing its changes in relation to kidney function, flares, and interstitial fibrosis. Methods: Overall, 132 SLE patients (57 with LN) were included and prospectively followed up for at least 36 months. DKK3 was measured in serum at baseline. Biopsies were evaluated for glomerular involvement, interstitial fibrosis, and tubular atrophy. Results: Patients with biopsy-proven LN had significantly higher levels of DKK3 than those without (median [min–max]: 215 ng/mL [81–341] vs. 21.1 ng/mL [1–69], p < 0.01). DKK3 levels were associated with prevalent chronic kidney diseases (OR: 4.31 [C.I. 2.01–6.61] per DKK3 doubling, p < 0.01), higher chronicity index at biopsy (1.75 [1.51–2.77] per DKK3 doubling, p < 0.01), and flares rate (OR: 1.45 [C.I. 1.1–5.71] per DKK3 doubling, p < 0.044). Conclusions: While kidney biopsy still represents the gold standard for diagnostic and prognostic assessment in LN, DKK3 could represent an additional prognostic tool to monitor SLE patients and guide therapeutic choices.

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Dziamałek-Macioszczyk, Paulina, Agata Winiarska, Anna Pawłowska, Paweł Wojtacha, and Tomasz Stompór. "Patterns of Dickkopf-3 Serum and Urine Levels at Different Stages of Chronic Kidney Disease." Journal of Clinical Medicine 12, no. 14 (July 15, 2023): 4705. http://dx.doi.org/10.3390/jcm12144705.

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Dickkopf 3 (Dkk3) is a WNT/β-catenin signaling pathway regulator secreted by tubular epithelial cells upon the influence of different stressors. Recently Dkk3 was described as a biomarker of tubular cell injury and a tool that may estimate the risk of chronic kidney disease (CKD) progression. The data about Dkk3 concentrations at particular stages of CKD are lacking. The aim of this study was to measure serum and urine Dkk3 levels in patients with different ‘renal status’ and evaluate its role as a biomarker of renal damage. One hundred individuals, aged between 24 and 85 years (mean 53.1 ± 17.1), were enrolled in the study. Five groups of 20 subjects each were recruited based on their kidney function. Serum and urine Dkk3 levels were measured by ELISA. The highest median urinary Dkk3 normalized to urinary creatinine was found in patients with established CKD (7051 pg/mg). It was two times higher in renal transplant patients (5705 pg/mg) than in healthy individuals (2654 pg/mg) and the glomerulonephritis group (2470 pg/mg). Urinary Dkk3 was associated with serum creatinine in participants with established CKD and following transplantation. Our results confirm the potential role of Dkk3 as a biomarker of an ongoing renal injury.

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Zhang, Yingjie, Huibo Li, Rongyi Cao, Lili Sun, Yan Wang, Shengjin Fan, Yanqiu Zhao та ін. "Suppression of Mir-708 Promotes DKK3 to Inhibit Wnt/β-Catenin Signaling Pathway in Adult B-ALL". Blood 128, № 22 (2 грудня 2016): 5090. http://dx.doi.org/10.1182/blood.v128.22.5090.5090.

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Abstract Dickkopf-3 (DKK-3) is a Wnt signaling antagonist, and DKK3 inactivation is associated with poor prognosis in various solid tumors and hematologic malignancies. Epigenetic hypermethylation has been implicated in downregulation of DKK3, but other regulatory mechanisms remain to be investigated. In this study, we examined DKK3 expression and the role of microRNA in the regulation of DKK3 in adult B-ALL. Our results showed low levels of DKK3 expression in Nalm-6 and BALL-1 cell lines, and leukemia cells from adult B-ALL patients. DKK3 expression was remarkably lower in the initial diagnosis and relapse samples than in the matched samples during remission. In addition to hypermethylation, low levels of DKK3 were associated with high expression of miR-708. This finding was similar to that in childhood ALL. The miR-708 was predicted to bind to the 3'-UTR of DKK3. By using miR-708 mimics, we found that miR-708 targets DKK3 to promote B-ALL cell proliferation through cell cycle promotion and apoptosis inhibition. The treatment with 5-aza-2'-deoxycytidine significantly increased DKK3 and decreased p-GSK3β, cyclin D1 and nuclear and cytoplasmic β-catenin protein expression. A synergistic effect was seen when the miR-708 inhibitor and 5-aza were used simultaneously. Although miR-708 was reported to either promote or suppress tumorigenecity in some solid tumors, our findings indicate that suppression of miR-708 increases DKK3 expression to inhibit the Wnt/β- catenin signaling pathway in B-ALL. Disclosures No relevant conflicts of interest to declare.

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Inamoto, Yoshihiro, Paul J. Martin, Stephanie J. Lee, Amin A. Momin, Laura Tabellini, Lynn E. Onstad, Joseph Pidala, et al. "Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation." Blood Advances 4, no. 11 (June 3, 2020): 2409–17. http://dx.doi.org/10.1182/bloodadvances.2020001485.

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Abstract To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD.

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Zhou, Liran, Hongmei Husted, Todd Moore, Mason Lu, Defeng Deng, Yan Liu, Vijaya Ramachandran, et al. "Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma." Science Translational Medicine 10, no. 464 (October 24, 2018): eaat3487. http://dx.doi.org/10.1126/scitranslmed.aat3487.

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Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-κB activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8+ T cells, and more than doubled survival. Treatment with a DKK3-blocking monoclonal antibody inhibited PDAC progression and chemoresistance and prolonged survival. The combination of DKK3 inhibition with immune checkpoint inhibition was more effective in reducing tumor growth than either treatment alone and resulted in a durable improvement in survival, suggesting that DKK3 neutralization may be effective as a single targeted agent or in combination with chemotherapy or immunotherapy for PDAC.

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Sciascia, S., M. Radin, A. Barinotti, I. Cecchi, D. Rossi, R. Fenoglio, and D. Roccatello. "POS1448 DICKKOPF HOMOLOG 3 (DKK3) AS A PROGNOSTIC MARKER IN LUPUS NEPHRITIS: A PROSPECTIVE MONOCENTRIC EXPERIENCE." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1069.1–1069. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1254.

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BackgroundLupus nephritis (LN) is a major cause of mortality/morbidity in patients affected by systemic lupus erythematosus (SLE). Reliable prognostic markers, especially related to the degree of interstitial fibrosis, are still lacking and renal biopsy still represents the gold standard. Recent data suggests a role of Dickkopf homolog 3 (DKK3) as a marker of tissue fibrosis in different diseases, however its role in autoimmune diseases still needs to be elucidated.ObjectivesTo investigate DKK3 serum levels in SLE patients with and without LN, assessing its changes in relation to kidney function, flares and interstitial renal fibrosis, as well as its association with the IFN signature.Methods132 SLE patients, 57 of whom diagnosed with LN, were included in this study, as well as 50 healthy donors. DKK3 and Myxovirus resistance protein 1 (MxA) were measured in serum samples, using enzyme-linked immunosorbent assays. Biopsies were evaluated for glomerular involvement, interstitial renal fibrosis and tubular atrophy according to 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification and the revised 2018 version. Patients were followed-up for at least 36 months.ResultsDKK3 serum levels were significantly higher in patients with biopsy-proven LN when compared to those without (median[min-max]: 215ng/ml [81-341] vs 21.1ng/ml [1-69], p<0.01). When focusing on patients with LN, DKK3 levels resulted to be associated with the presence of chronic kidney disease (OR: 4.31[C.I. 2.01-6.61] per DKK3 doubling, p<0.01), higher chronicity index at biopsy (OR: 1.75[C.I. 1.59-2.13] per DKK3 doubling, p<0.01) and flares rate (OR: 1.45[C.I. 1.1-5.71] per DKK3 doubling, p<0.044). DKK3 levels correlated with the IFN signature as expressed by MxA (correlation coefficient: 0.71, p<0.037).ConclusionWhile kidney biopsy remains the gold standard for diagnostic and prognostic assessment in LN, DKK3 could represent an additional useful prognostic tool to monitor SLE patients and eventually to guide therapeutic choices.Disclosure of InterestsNone declared

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Lim, Xinhong, Si Hui Tan, Ka Lou Yu, Sophia Beng Hui Lim та Roeland Nusse. "Axin2 marks quiescent hair follicle bulge stem cells that are maintained by autocrine Wnt/β-catenin signaling". Proceedings of the National Academy of Sciences 113, № 11 (22 лютого 2016): E1498—E1505. http://dx.doi.org/10.1073/pnas.1601599113.

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How stem cells maintain their identity and potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem cells can enter an extended period of quiescence during the resting phase but retain stem cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge cells causes them to lose their stem cell potency to contribute to hair growth and undergo premature differentiation instead. Bulge cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem cell potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge cells reinforces differentiation.

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Nguyen, Que Thanh Thanh, Hwang Shin Park, Tae Jin Lee, Kyung-Mi Choi, Joong Yull Park, Daehan Kim, Jae Hyung Kim, Junsoo Park та Eun-Ju Lee. "DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway". Cancers 14, № 4 (12 лютого 2022): 924. http://dx.doi.org/10.3390/cancers14040924.

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Dickkopf-3 (DKK3), a tumor suppressor, is frequently downregulated in various cancers. However, the role of DKK3 in ovarian cancer has not been evaluated. This study aimed to assess aberrant DKK3 expression and its role in epithelial ovarian carcinoma. DKK3 expression was assessed using immunohistochemistry with tissue blocks from 82 patients with invasive carcinoma, and 15 normal, 19 benign, and 10 borderline tumors as controls. Survival data were analyzed using Kaplan–Meier and Cox regression analysis. Paclitaxel-resistant cells were established using TOV-21G and OV-90 cell lines. Protein expression was assessed using Western blotting and immunofluorescence analysis. Cell viability was assessed using the MT assay and 3D-spheroid assay. Cell migration was determined using a migration assay. DKK3 was significantly downregulated in invasive carcinoma compared to that in normal, benign, and borderline tumors. DKK3 loss occurred in 56.1% invasive carcinomas and was significantly associated with disease-free survival and chemoresistance in serous adenocarcinoma. DKK3 was lost in paclitaxel-resistant cells, while β-catenin and P-glycoprotein were upregulated. Exogenous secreted DKK3, incorporated by cells, enhanced anti-tumoral effect and paclitaxel susceptibility in paclitaxel-resistant cells, and reduced the levels of active β-catenin and its downstream P-glycoprotein, suggesting that DKK3 can be used as a therapeutic for targeting paclitaxel-resistant cancer.

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Caffo, Maria, Roberta Fusco, Rosalba Siracusa, Gerardo Caruso, Valeria Barresi, Rosanna Di Paola, Salvatore Cuzzocrea, Antonino Francesco Germanò, and Salvatore Massimo Cardali. "Molecular Investigation of DKK3 in Cerebral Ischemic/Reperfusion Injury." Biomedicines 11, no. 3 (March 7, 2023): 815. http://dx.doi.org/10.3390/biomedicines11030815.

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Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. Its role in the mechanisms of cellular degeneration and protection is still unknown. The aim of our work is to investigate the endogenous activation of the DKK3 pathway in a model of transient occlusion of the middle cerebral artery in rats. In particular, the animals were subjected to 1 h of ischemia followed by different reperfusion times (1 h, 6 h, 12 h and 24 h) to evaluate the downstream pathway and the time course of its activation. Western blot analysis showed increased Dkk3 expression in animals with the highest time of reperfusion. The increased levels of Dkk3 were accompanied by reduced Wnt3a, Frz1 and PIWI1a expression in the cytosol while FOXM1 and β-catenin decreased in the nucleus. These molecular changes led to an increase in the apoptotic pathway, as showed by the increased expression of Caspase 3 and Bax and the reduced levels of Bcl-2, and to a decrease in neurogenesis, as shown by the decreased expression of Tbr2, Ngn2 and Pax6. In the second part of the study, we decided to employ curcumin, an activator of the Wnt/β-catenin signaling, to investigate its effect on Dkk3. In particular, curcumin was administered 1 and 6 h after ischemia, and animals were sacrificed 24 h later when the expression of Dkk3 was higher. Our data displayed that curcumin administration decreased Dkk3 expression, and increased Wnt3a, Frz1 and PIWI1a levels. Well in line with these data, curcumin administration increased nuclear β-catenin and FOXM1 expression. The down-regulation of Dkk3 by curcumin led to reduced apoptosis and increased neurogenesis. Summarizing, our results showed that Dkk3 acts as an inhibitor of Wnt/β-catenin signaling during cerebral ischemia. Additionally, its inhibition and the contextual activation of the Wnt/β-catenin pathway are protective against ischemic stroke.

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Hamzehzadeh, Leila, Michele Caraglia, Stephen L. Atkin, and Amirhossein Sahebkar. "Dickkopf homolog 3 (DKK3 ): A candidate for detection and treatment of cancers?" Journal of Cellular Physiology 233, no. 6 (January 15, 2018): 4595–605. http://dx.doi.org/10.1002/jcp.26313.

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Xue, Ruizhi, Wenfeng Lin, Hirofumi Fujita, Jingkai Sun, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, et al. "Dkk3/REIC Deficiency Impairs Spermiation, Sperm Fibrous Sheath Integrity and the Sperm Motility of Mice." Genes 13, no. 2 (January 31, 2022): 285. http://dx.doi.org/10.3390/genes13020285.

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The role of Dickkopf-3 (Dkk3)/REIC (The Reduced Expression in Immortalized Cells), a Wnt-signaling inhibitor, in male reproductive physiology remains unknown thus far. To explore the functional details of Dkk3/REIC in the male reproductive process, we studied the Dkk3/REIC knock-out (KO) mouse model. By examining testicular sections and investigating the sperm characteristics (count, vitality and motility) and ultrastructure, we compared the reproductive features between Dkk3/REIC-KO and wild-type (WT) male mice. To further explore the underlying molecular mechanism, we performed RNA sequencing (RNA-seq) analysis of testicular tissues. Our results showed that spermiation failure existed in seminiferous tubules of Dkk3/REIC-KO mice, and sperm from Dkk3/REIC-KO mice exhibited inferior motility (44.09 ± 8.12% vs. 23.26 ± 10.02%, p < 0.01). The Ultrastructure examination revealed defects in the sperm fibrous sheath of KO mice. Although the average count of Dkk3/REIC-KO epididymal sperm was less than that of the wild-types (9.30 ± 0.69 vs. 8.27 ± 0.87, ×106), neither the gap (p > 0.05) nor the difference in the sperm vitality rate (72.83 ± 1.55% vs. 72.50 ± 0.71%, p > 0.05) were statistically significant. The RNA-seq and GO (Gene Oncology) enrichment results indicated that the differential genes were significantly enriched in the GO terms of cytoskeleton function, cAMP signaling and calcium ion binding. Collectively, our research demonstrates that Dkk3/REIC is involved in the process of spermiation, fibrous sheath integrity maintenance and sperm motility of mice.

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Haug, Bjørn Helge, Jørn R. Henriksen, Jochen Buechner, Dirk Geerts, Ellen Tømte, Per Kogner, Tommy Martinsson, Trond Flægstad, Baldur Sveinbjørnsson, and Christer Einvik. "MYCN-regulated miRNA-92 inhibits secretion of the tumor suppressor DICKKOPF-3 (DKK3) in neuroblastoma." Carcinogenesis 32, no. 7 (May 13, 2011): 1005–12. http://dx.doi.org/10.1093/carcin/bgr073.

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Schäfer, Ann-Kathrin C., Dennis Pieper, Hassan Dihazi, Gry H. Dihazi, Stephan Lüders, Michael J. Koziolek, and Manuel Wallbach. "Urinary Dickkopf-3 (DKK3) Is Associated with Greater eGFR Loss in Patients with Resistant Hypertension." Journal of Clinical Medicine 12, no. 3 (January 29, 2023): 1034. http://dx.doi.org/10.3390/jcm12031034.

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Patients with resistant hypertension (HTN) demonstrate an increased risk of chronic kidney disease and progression to end-stage renal disease; however, the individual course of progression is hard to predict. Assessing the stress-induced, urinary glycoprotein Dickkopf-3 (uDKK3) may indicate ongoing renal damage and consecutive estimated glomerular filtration rate (eGFR) decline. The present study aimed to determine the association between uDKK3 levels and further eGFR changes in patients with resistant HTN. In total, 31 patients with resistant HTN were included. Blood pressure and renal function were measured at baseline and up to 24 months after (at months 12 and 24). uDKK3 levels were determined exclusively from the first available spot urine sample at baseline or up to a period of 6 months after, using a commercial ELISA kit. Distinctions between different patient groups were analyzed using the unpaired t-test or Mann–Whitney test. Correlation analysis was performed using Spearman’s correlation. The median uDKK3 level was 303 (interquartile range (IQR) 150–865) pg/mg creatinine. Patients were divided into those with high and low eGFR loss (≥3 vs. <3 mL/min/1.73 m²/year). Patients with high eGFR loss showed a significantly higher median baseline uDKK3 level (646 (IQR 249–2555) (n = 13) vs. 180 (IQR 123–365) pg/mg creatinine (n = 18), p = 0.0412 (Mann–Whitney U)). Alternatively, patients could be classified into those with high and low uDKK3 levels (≥400 vs. <400 pg/mg creatinine). Patients with high uDKK3 levels showed significantly higher eGFR loss (−6.4 ± 4.7 (n = 11) vs. 0.0 ± 7.6 mL/min/1.73 m2/year (n = 20), p = 0.0172 (2-sided, independent t-test)). Within the entire cohort, there was a significant correlation between the uDKK3 levels and change in eGFR at the latest follow-up (Spearman’s r = −0.3714, p = 0.0397). In patients with resistant HTN, high levels of uDKK3 are associated with higher eGFR loss up to 24 months later.

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Wang, Xiao-Yang, Yuzhi Yin, Hongyan Yuan, Toshiyuki Sakamaki, Hideyuki Okano, and Robert I. Glazer. "Musashi1 Modulates Mammary Progenitor Cell Expansion through Proliferin-Mediated Activation of the Wnt and Notch Pathways." Molecular and Cellular Biology 28, no. 11 (March 24, 2008): 3589–99. http://dx.doi.org/10.1128/mcb.00040-08.

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ABSTRACT The RNA-binding protein Musashi1 (Msi1) is a positive regulator of Notch-mediated transcription in Drosophila melanogaster and neural progenitor cells and has been identified as a putative human breast stem cell marker. Here we describe a novel functional role for Msi1: its ability to drive progenitor cell expansion along the luminal and myoepithelial lineages. Expression of Msi1 in mammary epithelial cells increases the abundance of CD24hi Sca-1+, CD24hi CD29+, CK19, CK6, and double-positive CK14/CK18 progenitor cells. Proliferation is associated with increased proliferin-1 (PLF1) and reduced Dickkopf-3 (DKK3) secretion into the conditioned medium from Msi-expressing cells, which is associated with increased colony formation and extracellular signal-regulated kinase (ERK) phosphorylation. Treatment with the MEK inhibitor U0126 inhibits ERK activation and decreases Notch and β-catenin/T-cell factor (TCF) reporter activity resulting from Msi1 expression. Reduction of DKK3 in control cells with a short hairpin RNA (shRNA) increases Notch and β-catenin/TCF activation, whereas reduction of PLF1 with a shRNA in Msi1-expressing cells inhibits these pathways. These results identify Msi1 as a key determinant of the mammary lineage through its ability to coordinate cell cycle entry and activate the Notch and Wnt pathways by a novel autocrine process involving PLF1 and DKK3.

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Srinivasan, Dharini, Frank Arnold, Elodie Roger, Anna Härle, Michael Melzer, Patrick Hermann, Lukas Perkhofer, Johann Gout, and Alexander Kleger. "Abstract C028: DKK3 in pancreatic cancer – Elucidating the roles of a double-edged sword." Cancer Research 84, no. 2_Supplement (January 16, 2024): C028. http://dx.doi.org/10.1158/1538-7445.panca2023-c028.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly challenging disease with a poor prognosis due to high tumor heterogeneity, lack of diagnostic biomarkers and limited treatment options. Therefore, it is crucial to meticulously examine the intricate molecular mechanisms involved in the interplay between different cellular compartments in PDAC. We previously identified DKK3 (Dickkopf-3) as a novel factor promoting organ regeneration during pancreatitis and established a previously unknown link between DKK3 and the Wnt and Hedgehog signaling. Given that pancreatitis is a significant risk factor for pancreatic cancer, we were motivated to investigate the potential role of DKK3 in PDAC development. We utilized PDAC mouse models driven by LSL-KrasG12D/+; Ptf1aCre/+ with or without homozygous/heterozygous DKK3 deletion in both epithelial and stromal compartment and employed various in vitro and ex vivo systems to examine the stage and compartment-specific roles of DKK3 during PDAC progression. Through a comprehensive and time-resolved analysis of tumor characteristics, we discovered that the loss of DKK3 led to rapid oncogenic transformation, marked by a significant increase in metaplasia and desmoplasia starting at an early stage (10 weeks). Ex vivo acinar-to-ductal metaplasia assay and rescue experiments with wildtype and DKK3-null acinar cells revealed that secreted DKK3 operates as a tumor suppressive roadblock in PDAC-initiating steps. This advanced preneoplastic stage translated into accelerated progression toward invasive tumors at 36 weeks, shortened overall survival, and a higher liver metastasis incidence in the DKK3-null animals at the endpoint. Further characterization of isolated tumor cells underpinned our observations, revealing prominent mesenchymal features and enhanced migratory capacities upon loss of DKK3. Interestingly, DKK3-null PDACs exhibited a pronounced stroma remodeling with a myofibroblastic cancer-associated fibroblast-enriched environment, as well as an immunosuppressive stroma with abundant regulatory T cells and cytotoxic T cell depletion, as substantiated by coculture experiments. Intriguingly, while displaying similar phenotypic features to DKK3-null tumors, Dkk3+/- heterozygotes exhibited the most aggressive outcome. To further dissect this finding, we conducted a set of in silico approaches and immunostainings revealing persistent stromal DKK3 expression in DKK3-proficient PDACs. This suggested a possible dual role of DKK3 that could operate either as a friend or a foe depending on its spatiotemporal expression in PDAC. In line, in vitro systems demonstrated a distinct oncogenic effect of DKK3 on endpoint tumor cells, particularly promoting malignant cell migration. In summary, we propose that epithelial DKK3 exerts cell-autonomous tumor suppressive functions during PDAC onset, while stromal DKK3 acts as an oncogenic cue driving cancer progression. These findings highlight DKK3 as a promising biomarker and a novel therapeutic target for addressing the oncogenic dialog within PDAC tumors. Citation Format: Dharini Srinivasan, Frank Arnold, Elodie Roger, Anna Härle, Michael Melzer, Patrick Hermann, Lukas Perkhofer, Johann Gout, Alexander Kleger. DKK3 in pancreatic cancer – Elucidating the roles of a double-edged sword [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C028.

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Cisa, S., A. Martinez-Limon, T. Dediulia, X. Leon, J. Ubeda, J. M. Nomdedu, A. Villanueva, and M. Parreño. "590: Dickkopf-3 (DKK3), biomarker in head and neck cancer and its implication in tumor progression." European Journal of Cancer 50 (July 2014): S142. http://dx.doi.org/10.1016/s0959-8049(14)50525-4.

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Kamal, Hiba R., and Thikra A. Allwsh. "Evaluating the effect of vitamin D3 supplementation on DKK-3 serum for third-stage chronic kidney patients." Pharmacia 71 (June 13, 2024): 1–6. http://dx.doi.org/10.3897/pharmacia.71.e127441.

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Vitamin D3 helps to reduce oxidative stress levels, as does Dickkopf-3 (DKK-3) glycoprotein, which is released in the kidney’s tubular membrane during stress and helps promote tubulointerstitial fibrosis. The aim is to investigate how vitamin D supplementation affects serum DKK-3 levels and biochemical indicators of renal function in CKD patients in stage III. The study had inclusion criteria for 180 participants of both sexes, aged between 20 and 35 years. They were divided into 3 groups: 60 healthy participants as control, 60 CKD patients in stage III (without vitamin D3 supplements), and 60 others (with three months of 5,000 IU of weekly vitamin D3 supplements). DKK-3 levels in serum, vitamin D3, and parathyroid hormone were examined, and kidney function was tested. Findings indicated a significant increase in levels of DKK-3 serum for patients in the 2 and 3 groups with CKD compared with control. Additionally, outcomes revealed significantly lower DKK-3 (41%) in the third group of patients who took vitamin D compared to the second group (120%) without vitamin D supplements. There was also an improvement in several kidney functions for the third group, and the relationships revealed a significant inverse association between the levels of vitamin D3 and serum DKK3. Also, there is a significant inverse association with urea and creatinine levels; additionally, there is a significant positive association with glomerular filtration rate and calcium. In conclusion, DKK-3 may be a potential biomarker for the development of CKD. Furthermore, vitamin D administration improved kidney function and DKK-3 levels in individuals with stage III CKD. As a result, vitamin D can assist in reducing the development of chronic kidney disease.

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WANG, ZHENG, LI-JUN MA, YI KANG, XIAO LI та XIAO-JU ZHANG. "Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway". Oncology Reports 33, № 3 (30 грудня 2014): 1097–106. http://dx.doi.org/10.3892/or.2014.3704.

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Karamariti, Eirini, Chungang Zhai, Baoqi Yu, Lei Qiao, Zhihong Wang, Claire M. F. Potter, Mei Mei Wong, et al. "DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells." Arteriosclerosis, Thrombosis, and Vascular Biology 38, no. 2 (February 2018): 425–37. http://dx.doi.org/10.1161/atvbaha.117.310079.

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Lorsy, E., J. Veeck, R. Knüchel, and E. Dahl. "361: The putative tumor suppressor gene Dickkopf-3 (DKK3) and its role in the carcinogenesis of breast cancer." European Journal of Cancer 50 (July 2014): S86. http://dx.doi.org/10.1016/s0959-8049(14)50321-8.

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Zhou, Shanghui, Yun Zhu, Mubarak Mashrah, Xinyu Zhang, Zhijing He, Zhigang Yao, Chunye Zhang, Feng Guo, Yongjie Hu, and Chenping Zhang. "Expression pattern of DKK3, dickkopf WNT signaling pathway inhibitor 3, in the malignant progression of oral submucous fibrosis." Oncology Reports 37, no. 2 (December 8, 2016): 979–85. http://dx.doi.org/10.3892/or.2016.5307.

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Yin, De-tao, Wenxun Wu, Mingchuang Li, Qi-en Wang, Hongqiang Li, Yongfei Wang, Yifeng Tang, and Mingzhao Xing. "DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma." Endocrine-Related Cancer 20, no. 4 (May 23, 2013): 507–14. http://dx.doi.org/10.1530/erc-13-0053.

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The expression of the Dickkopf homolog 3 (DKK3) gene is downregulated in some human cancers, suggesting a possible tumor suppressor role of this gene. The role and regulation ofDKK3in thyroid cancer have not been examined. In this study, we explored the relationship of promoter methylation with the inactivation ofDKK3and tumor behaviors in papillary thyroid carcinoma (PTC). We used methylation-specific PCR and RT-PCR to examine the promoter methylation and expression ofDKK3and tumor characteristics. We found mRNA expression ofDKK3in 44.9% of the PTC tissue samples vs 100% of the matched normal thyroid tissue samples (P<0.01). In contrast, an opposite distribution pattern ofDKK3gene methylation was observed; specifically, 38.8% of the PTC tissue samples vs 0% of the matched normal thyroid tissue samples harboredDKK3methylation. An inverse correlation between the promoter methylation and mRNA expression ofDKK3in PTC tissue samples was also observed. Moreover, we also found an inverse correlation betweenDKK3expression and some aggressive pathological characteristics of PTC, including high TNM stages and lymph node metastasis, but a positive correlation betweenDKK3promoter hypermethylation and pathological aggressiveness of the tumor. Treatment of the PTC cell line TPC-1 with the demethylating agent 5-azaC reducedDKK3promoter methylation and enhanced its expression, establishing functionally the impact ofDKK3methylation on its expression. Our data thus for the first time demonstrate that theDKK3gene is a potential tumor suppressor gene in thyroid cancer and that aberrant promoter methylation is an important mechanism for its downregulation, which may play a role in the tumorigenesis and aggressiveness of PTC.

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Inoue, Junji, Hirofumi Fujita, Tetsuya Bando, Yoichi Kondo, Hiromi Kumon, and Hideyo Ohuchi. "Expression analysis of Dickkopf-related protein 3 (Dkk3) suggests its pleiotropic roles for a secretory glycoprotein in adult mouse." Journal of Molecular Histology 48, no. 1 (November 19, 2016): 29–39. http://dx.doi.org/10.1007/s10735-016-9703-2.

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Trotter, Timothy N., Delila Serra, Carina Dagotto, Tao Wang, Xiao Yang, Junping Wei, Gangjun Lei, H. Kim Lyerly, and Zachary C. Hartman. "Abstract 2451: Dormant mammary tumors resist antigen-specific killing and regulate systemic immunity in association with PTN and DKK3." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2451. http://dx.doi.org/10.1158/1538-7445.am2022-2451.

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Abstract Little is known regarding why the immune system is ineffective at eliminating certain disseminated/dormant tumor cells before overt metastatic recurrence. Previous findings revealed that the adaptive immune system reduces growth of proliferative D2A1 tumors in Balb/c versus SCID mice while dormant D2.1 tumors are largely unaffected by adaptive immunity, despite being significantly infiltrated by T cells. Therefore, the aim of the present study was to determine the downstream effects and molecular underpinnings of dormancy-mediated alterations to the immune environment. Experiments were performed using two independent clones of a spontaneous mammary tumor from a female Balb/c mouse that display varying degrees of dormancy in vivo. D2A1 cells grow rapidly upon orthotopic or systemic injection while D2.1 cells remain dormant long term in local and metastatic sites. Both cell lines were modified to express enhanced green fluorescent protein (eGFP) for use with Just eGFP Death Inducing (JeDI) T cells which contain a T cell receptor (TCR) targeted to eGFP200-208. Adoptive transfer of JeDI T cells caused complete rejection of D2A1-eGFP tumors in the mammary fat pad (MFP), while no difference in growth was observed in D2.1-eGFP tumors. Interestingly, contralateral MFP implantation of D2.1-eGFP tumors resulted in a partial rescue of D2A1-eGFP rejection suggesting systemic immune suppression by distant, dormant tumor cells. Bulk RNA-sequencing of D2A1 and D2.1 tumors revealed significant upregulation of pathways associated with immune activation and extracellular matrix (ECM) remodeling in dormant tumors. Further, Gene Set Enrichment Analysis (GSEA) showed an enrichment for signatures of mammary stem cells and luminal progenitor cells, as well as exhausted vs memory CD8 cells and T cell anergy, in D2.1 tumors. Of the top upregulated genes in D2.1 tumors, pleiotrophin (PTN) and Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) were chosen for further investigation. Overexpressing PTN or DKK3 in D2A1 cells significantly increased MFP tumor growth in Balb/c but not SCID mice. In addition, PTN or DKK3 overexpression altered both local and systemic T cell profiles, including decreased effector memory (CD62l-, CD44+) and increased naïve (CD62l+, CD44-) CD4 and CD8 cells. Humoral immunity was also affected, as indicated by decreased eGFP-specific antibodies in serum from mice bearing PTN or DKK3 overexpressing tumors. Conversely, knocking down PTN or DKK3 in D2.1 cells had the opposite effect on systemic immunity. Taken together, these data indicate that dormant tumors can resist antigen-specific killing by CD8 T cells despite high T cell infiltration, and possibly suppress antigen-specific immunity in distant tumor sites. Moreover, both PTN and DKK3 emerge as potential mediators of dormancy-induced immune evasion. Citation Format: Timothy N. Trotter, Delila Serra, Carina Dagotto, Tao Wang, Xiao Yang, Junping Wei, Gangjun Lei, H. Kim Lyerly, Zachary C. Hartman. Dormant mammary tumors resist antigen-specific killing and regulate systemic immunity in association with PTN and DKK3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2451.

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Tom, Irene, Victoria C. Pham, Kenneth J. Katschke, Wei Li, Wei-Ching Liang, Johnny Gutierrez, Andrew Ah Young, et al. "Development of a therapeutic anti-HtrA1 antibody and the identification of DKK3 as a pharmacodynamic biomarker in geographic atrophy." Proceedings of the National Academy of Sciences 117, no. 18 (April 28, 2020): 9952–63. http://dx.doi.org/10.1073/pnas.1917608117.

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Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have developed an HtrA1-blocking Fab fragment to test the therapeutic hypothesis that HtrA1 protease activity is involved in the progression of AMD. Next, we generated an activity-based small-molecule probe (ABP) to track target engagement in vivo. In addition, we used N-terminomic proteomic profiling in preclinical models to elucidate the in vivo repertoire of HtrA1-specific substrates, and identified substrates that can serve as robust pharmacodynamic biomarkers of HtrA1 activity. One of these HtrA1 substrates, Dickkopf-related protein 3 (DKK3), was successfully used as a biomarker to demonstrate the inhibition of HtrA1 activity in patients with AMD who were treated with the HtrA1-blocking Fab fragment. This pharmacodynamic biomarker provides important information on HtrA1 activity and pharmacological inhibition within the ocular compartment.

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Zhang, Li, Caixian Sun, Yaxi Jin, Kai Gao, Xudong Shi, Wenying Qiu, Chao Ma та Lianfeng Zhang. "Dickkopf 3 (Dkk3) Improves Amyloid-β Pathology, Cognitive Dysfunction, and Cerebral Glucose Metabolism in a Transgenic Mouse Model of Alzheimer’s Disease". Journal of Alzheimer's Disease 60, № 2 (18 вересня 2017): 733–46. http://dx.doi.org/10.3233/jad-161254.

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Das, Deepika Sharma, Neerja Wadhwa, Neetu Kunj, Kanchan Sarda, Bhola Shankar Pradhan та Subeer S. Majumdar. "Dickkopf Homolog 3 (DKK3) Plays a Crucial Role Upstream of WNT/β-CATENIN Signaling for Sertoli Cell Mediated Regulation of Spermatogenesis". PLoS ONE 8, № 5 (7 травня 2013): e63603. http://dx.doi.org/10.1371/journal.pone.0063603.

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Piek, Arnold, Navin Suthahar, Adriaan A. Voors, Rudolf A. Boer, and Herman H. W. Silljé. "A combined bioinformatics, experimental and clinical approach to identify novel cardiac‐specific heart failure biomarkers: is Dickkopf ‐3 ( DKK3 ) a possible candidate?" European Journal of Heart Failure 22, no. 11 (September 22, 2020): 2065–74. http://dx.doi.org/10.1002/ejhf.1988.

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Schunk, Stefan J., Danilo Fliser, and Thimoteus Speer. "Urinary Dickkopf-3 (DKK3) Uncovers Unapparent Progressive Kidney Injury in Patients with Chronic Obstructive Pulmonary Disease: An Etiological Study and Experimental Validation." Journal of the American Society of Nephrology 32, no. 10S (October 2021): 849. http://dx.doi.org/10.1681/asn.20213210s1849c.

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Trotter, Timothy N., Delila Serra, Carina Dagotto, Tao Wang, Xiao Yang, Junping Wei, Gangjun Lei, H. Kim Lyerly, and Zachary C. Hartman. "Abstract PR015: Dormant mammary tumors persist long-term despite adaptive immunity by establishing a Treg-dominated niche via DKK3." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): PR015. http://dx.doi.org/10.1158/1538-7445.metastasis22-pr015.

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Abstract A significant portion of breast cancer survivors eventually experience locoregional or metastatic recurrence. It is clear that the adaptive immune system controls proliferative tumor outgrowth, but how dormant tumor cells escape to eventually form new lesions remains unclear. Previous studies showed that proliferative D2A1 or D2.OR tumors are restricted by adaptive immunity in Balb/c versus SCID mice whereas dormant D2.1 tumors are largely unaffected. Further, D2.1 tumors are highly infiltrated with T cells, particularly CD4+ cells and Tregs. Thus, the aim of the present study was to determine the extent to which dormant D2.1 tumors evade antigen-specific immunity and how these tumors shape the T cell niche. Experiments were performed using Balb/c syngeneic D2 mammary tumor cells – D2A1 cells grow rapidly upon orthotopic injection, D2.OR cells proliferate but to a lesser degree than D2A1, and D2.1 cells remain dormant long term. Cells were also modified to express enhanced green fluorescent protein (eGFP) for use with Just eGFP Death Inducing (JeDI) T cells containing a T cell receptor (TCR) targeted to eGFP200-208. Transfer of JeDI T cells caused complete rejection of D2A1-eGFP tumors in the mammary fat pad (MFP) while no difference was observed in D2.1-eGFP tumors. In contrast, treatment with anti-CTLA4 alone, anti-PD-1 alone, or combined anti-CTLA4/PD-1 reduced D2.1 tumor progression compared to isotype control. Whole JeDI splenocytes were also stimulated in vitro with eGFP200-208 peptide in the presence of D2A1 or D2.1 conditioned medium (CM). Surprisingly, while CD8 cells proliferated in both D2A1 and D2.1 CM, CD4+ T cells also proliferated in D2.1 CM and the Treg fraction of CD4+ cells was significantly elevated in D2.1 CM compared to D2A1 CM or control medium. RNA-sequencing confirmed substantial immune activity in D2.1 tumors compared to D2A1. D2.1 tumors also displayed a hybrid epithelial/mesenchymal (E/M) phenotype and expressed genes associated with both mammary epithelium (Krt8, Krt14, Cdh1) and mesenchymal cells (Itga5, Snai2, Notch1, Zeb1). Moreover, Gene Set Enrichment Analysis (GSEA) showed an enrichment of mammary stem and luminal progenitor cell signatures in D2.1 tumors. Of the top upregulated genes, Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) was chosen for further investigation. Interestingly, increased CD8 proliferation and IFNγ production, but decreased CD4 and Treg abundance, was observed in DKK3 shRNA knockdown (k/d) D2.1 CM compared to shScramble control. In vivo, overexpressing DKK3 in D2A1 cells significantly increased MFP tumor growth in Balb/c but not SCID mice, altered T cell activation locally and systemically, and decreased eGFP-specific antibodies. Similar results were observed in DKK3-overexpressing D2.OR tumors. Conversely, DKK3 k/d in D2.1 cells resulted in ~60% complete tumor rejection. Together, these data indicate that CD4 cells, particularly Tregs, are crucial in establishing a protective niche for long-term tumor dormancy with tumor-derived DKK3 emerging as a mediator of the Treg niche. Citation Format: Timothy N. Trotter, Delila Serra, Carina Dagotto, Tao Wang, Xiao Yang, Junping Wei, Gangjun Lei, H. Kim Lyerly, Zachary C. Hartman. Dormant mammary tumors persist long-term despite adaptive immunity by establishing a Treg-dominated niche via DKK3 [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR015.

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Zhang, Jin. "Chemotherapy-elicited exosomal miR-378a-3p and miR-378d to promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e12615-e12615. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e12615.

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e12615 Background: Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemo-elicited exosomes in regulating chemoresistance is poorly understood. Methods: Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results: Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome induced drug resistance in a nude mouse tumor xenograft model. Conclusions: This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.

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Eskander, R., S. Ali, H. Lankes, T. Dellinger, B. Hoang, N. Ramirez, B. Monk, J. Walker, E. Eisenhauer, and L. Randall. "Expression patterns of the Wnt pathway inhibitor dickKOPF-3 (Dkk3) and secreted frizzled-related proteins (sFRP) 1 and 4 in endometrial endometrioid adenocarcinoma: A gynecologic oncology group study." Gynecologic Oncology 127, no. 1 (October 2012): S5. http://dx.doi.org/10.1016/j.ygyno.2012.07.015.

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Charlier, E., O. Malaise, C. Deroyer, M. Zeddou, S. Neuville, G. Cobraiville, P. Gillet та ін. "Dickkopf 3 (Dkk3) is increased along human hip OA chondrocytes dedifferentiation and can modulate Wnt/Β-catenin and TGFβ Alk1/Smad1/5 signaling pathways, as well as leptin production". Osteoarthritis and Cartilage 24 (квітень 2016): S182. http://dx.doi.org/10.1016/j.joca.2016.01.359.

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Pratta, Michael, Angelina Volkova, Maureen Bleam, Rodica Morariu-Zamfir, Beth Rumberger, Stephen Douglass, Susan H. Smith, et al. "Janus Kinase (JAK) 1 Inhibition Results in Significant Changes in Serum Proteins and Peripheral T-Cell Populations That Correlated with Clinical Scores in Chronic Graft Versus Host Disease (GVHD) Patients (an Analysis from GRAVITAS-309)." Blood 142, Supplement 1 (November 28, 2023): 2197. http://dx.doi.org/10.1182/blood-2023-174955.

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Background: Chronic GVHD (cGVHD) occurs in 30-70% of allogeneic hematopoietic cell transplantation patients, and the rate has increased over the past 2 decades. Based on the degree of organ involvement, cGVHD is classified as mild, moderate, or severe. Standard treatment includes systemic corticosteroids (CS), together with immunosuppressive agents. GRAVITAS-309 (NCT03584516) was designed as a 2-part, multicenter, randomized trial to assess efficacy and safety of itacitinib, an orally bioavailable, selective JAK1 inhibitor, in combination with CS as first-line treatment for moderate to severe cGVHD. The dose-finding, open-label, randomized portion of the study initially investigated itacitinib at 200 mg once daily (qd) and 300 mg qd in combination with CS (methylprednisolone or prednisone); both doses were well tolerated. The trial was expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300 mg qd cohort was expanded and a CS monotherapy cohort was added. Results from the expanded portion of the study (n=139 patients) showed improved overall response rate (ORR) at 6 months in patients treated with itacitinib + CS vs CS alone (Im, et al. Blood 2022;140[Suppl 1]:1870). Here, we analyzed samples collected from patients in 4 cohorts (cohort A [300 mg qd], cohort B [400 mg qd], cohort C [300 mg bid], and cohort D [CS alone]) for systemic proteins and immune cell populations, to support investigation into the itacitinib mechanism of action and to correlate with clinical outcomes. Methods: Peripheral blood mononuclear cells (PBMCs) and serum were collected before treatment (baseline, day 1), and day 7, day 14 (PBMCs only), and day 28 following treatment initiation. Serum proteins were analyzed using the OLINK Target 96 platform, and circulating T-cell subsets were measured using flow cytometry of PBMCs and presented as a percentage of parent population. Samples were assessed irrespective of patients' response. Most of the patients (70-100% per cohort) with samples available for analysis were responders (achieved complete or partial responses). Results: Serum levels of proteins, including several proposed as potential prognostic cGVHD biomarkers, changed significantly at day 28 relative to baseline following treatment with itacitinib (Table 1). Levels of elafin, a marker of acute GVHD of the skin, were significantly reduced and levels of dickkopf-3 (DKK3), a marker of sclerotic and nonsclerotic cGVHD, were significantly increased in itacitinib cohorts only. Based on a repeated measures correlation analysis, both markers significantly correlated with overall clinical skin scores (elafin: r=+0.43; DKK3: r=-0.53; both P<0.001). Serum levels of other reported markers of cGVHD, including osteopontin, C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, were significantly decreased exclusively in itacitinib-treated cohorts, and not in the CS only cohort. Some proteins, including matrix metalloproteinase (MMP) 3, increased in all cohorts, suggesting that changes in these proteins cannot be attributed to itacitinib alone, but may reflect response to CS; other proteins, such as suppression of tumorigenicity (ST2), remained unchanged in response to treatment in all cohorts. CS treatment alone resulted in an increase in naive CD4 T cells (CD4 +CD8 ->CD45RA +CCR7 -) and a corresponding reduction of CD4 effector memory T cells (CD4 +CD8 ->CD45RA -CCR7 +) within 28 days (Figure 1, cohort D). Changes in naive CD4 T cells following CS monotherapy were significantly attenuated by itacitinib ( P<0.05 vs CS at day 28), particularly at the 400 mg qd dose (Figure 1, cohort B), which demonstrated the best ORR at 6 months (53% with 400 mg qd vs 36% with CS). Conclusions: Analysis of patient samples from GRAVITAS-309 revealed that serum elafin and DKK3 levels significantly correlated with skin GVHD scores, possibly reflecting the systemic origin of observed skin manifestations. Serum levels of osteopontin, CXCL9, and CXCL10 were specifically reduced by itacitinib in patients with cGVHD and may represent potential pharmacodynamic markers. Observed changes in different peripheral T-cell populations in patients' samples following itacitinib treatment were consistent with those reported in murine GVHD models, suggesting a potential role of naive CD4 + T cells in driving this disease. Planned future analyses will include identification of novel biomarkers that correlate with organ involvement.

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Al Shareef, Zainab, Mai Nidal Asad Ershaid, Rula Mudhafar, Sameh S. M. Soliman, and Robert M. Kypta. "Dickkopf-3: An Update on a Potential Regulator of the Tumor Microenvironment." Cancers 14, no. 23 (November 25, 2022): 5822. http://dx.doi.org/10.3390/cancers14235822.

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Dickkopf-3 (Dkk-3) is a member of the Dickkopf family protein of secreted Wingless-related integration site (Wnt) antagonists that appears to modulate regulators of the host microenvironment. In contrast to the clear anti-tumorigenic effects of Dkk-3-based gene therapies, the role of endogenous Dkk-3 in cancer is context-dependent, with elevated expression associated with tumor promotion and suppression in different settings. The receptors and effectors that mediate the diverse effects of Dkk-3 have not been characterized in detail, contributing to an ongoing mystery of its mechanism of action. This review compares the various functions of Dkk-3 in the tumor microenvironment, where Dkk-3 has been found to be expressed by subpopulations of fibroblasts, endothelial, and immune cells, in addition to epithelial cells. We also discuss how the activation or inhibition of Dkk-3, depending on tumor type and context, might be used to treat different types of cancers.

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Mourtada, Jana, Chloé Thibaudeau, Bohdan Wasylyk, and Alain C. Jung. "The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer." Cells 13, no. 1 (December 29, 2023): 75. http://dx.doi.org/10.3390/cells13010075.

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The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially modulation of the Wnt signaling pathway. DKK-3 is distinct, with its multifaceted roles in development, stem cell differentiation and tissue homeostasis. Intriguingly, DKK-3 appears to have immunomodulatory functions and a complex role in cancer, acting as either a tumor suppressor or an oncogene, depending on the context. DKK-3 is a promising diagnostic and therapeutic target that can be modulated by epigenetic reactivation, gene therapy and DKK-3-blocking agents. However, further research is needed to optimize DKK-3-based therapies. In this review, we comprehensively describe the known functions of DKK-3 and highlight the importance of context in understanding and exploiting its roles in health and disease.

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Fujita, Ken-ichi, Joong Su Kim, Laurel A. Eckhardt, John D. Shaughnessy, and Siegfried Janz. "Dkk1 Transgenic Mice for the Study of Bone Lesions in Human Multiple Myeloma." Blood 106, no. 11 (November 16, 2005): 2505. http://dx.doi.org/10.1182/blood.v106.11.2505.2505.

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Abstract Purpose: Extracellular antagonists of the cellular WNT signalling pathway can be divided into two classes depending on the mechanism by which ligand-receptor interactions are inhibited. Members of the first class including SFRP (secreted frizzled-related proteins), WIF1 (WNT inhibitory factor 1) and CER1 (cerberus homolog 1) bind to WNT proteins in the extracellular milieu. Members of the second class including Dickkopf (DKK) proteins bind to the WNT receptor subunits LRP5/6. Reduced WNT signalling may play a role in the natural history of the bone disease that is a hallmark of multiple myeloma (MM). Gene expression profiling of MM plasma cells has shown that over-expression of the Dickkopf family member DKK1 is linked with abundance and size of osteolytic lesions (N Engl J Med 2003, 349:2483–94). The biological mechanism of DKK1-mediated bone destruction is not known. Experimental procedure: To elucidate the mechanism by which DKK1 facilitates osteolysis, we generated transgenic mice in which mouse Dkk1 is expressed under control of the mouse immunoglobulin Eα enhancer. This enhancer is located 3′ of the immunoglobulin heavy-chain locus and comprised of four individual elements that span ~30 kb of genomic DNA. These elements were subcloned into a contiguous stretch of DNA, which we refer to as “reconstituted” Eα enhancer or HS1234 (Int Immunol 2001, 13:1003–12). Here we appended HS1234 to a Dkk1 cDNA whose expression is controlled by a mouse immunoglobulin VH promoter inserted 5′ of the transcriptional start site of Dkk1. Because of an internal ribosome entry site (IRES) 3′ of Dkk1, the gene encoding enhanced green fluorescence protein (EGFP) is co-expressed with Dkk1; i.e., it is a reporter of Dkk1 expression. A scheme of the structure of the Eα-Dkk1 transgene is depicted in Figure 1. Figure 1 Figure 1. Results: We generated 14 founder lines of Eα-Dkk1 transgenic mice that expressed Dkk1 and the EGFP-encoding gene by RT-PCR (Figure 2). Figure 2 Figure 2. The mice contained a variable number of Eα-Dkk1 copies, ranging from 2–3 to more than 100. There was but a loose association of transgene expression (qPCR of Dkk1 mRNA levels) and copy number (qPCR of genomic Ea-Dkk1 fragments); i.e., the high-copy number mice exhibited higher average mRNA levels than the low-copy number mice, although there were outliers in each group. Consistent with Eα-dependent restriction of Dkk1 expression to B/plasma cells, Dkk1 mRNA was readily detectable in lymphoid tissues, such as spleen, mesenteric lymph node and bone marrow, but not in liver. Conclusion: The newly developed Eα-Dkk1 transgenics may provide a valuable model system to elucidate DKK1-dependent bone disease in human MM.

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Denicol, A. C., K. B. Dobbs, and P. J. Hansen. "3 SEX INFLUENCES REGULATION OF GENE EXPRESSION BY DICKKOPF 1 IN THE BOVINE MORULA." Reproduction, Fertility and Development 27, no. 1 (2015): 94. http://dx.doi.org/10.1071/rdv27n1ab3.

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Successful embryonic development depends upon molecules secreted by the reproductive tract. Among such molecules is the protein dickkopf 1 (DKK1), an antagonist of canonical WNT signalling that can also activate the noncanonical, planar cell polarity (PCP) pathway. DKK1 increases the proportion of cells that are trophectoderm and hypoblast in the blastocyst and increases competence of embryos to establish pregnancy after transfer to recipients. The objective was to determine whether DKK1 affects cell fate by regulating expression of genes that promote differentiation at the morula stage, possibly by activating the PCP pathway. A second objective was to determine if actions of DKK1 on the embryonic transcriptome were dependent on embryo sex. Bovine oocytes were fertilized in vitro with pools of 3 bulls for which X- and Y-sorted sperm was available. Embryos were treated with 100 ng mL–1 DKK1 or vehicle at Day 5 of development and harvested 24 h later. Embryos were pooled in 5 replicates of 20 embryos each. Following RNA reverse-transcription and amplification, cDNA was used for microarray analysis of global gene expression using the Affymetrix® Bovine Gene 1.0 ST array (Affymetrix, Santa, Clara, CA, USA). Statistical analysis was performed by ANOVA using JMP® Genomics (SAS Institute, Cary, NC, USA). A total of 9931 transcripts were identified as being expressed. Differentially expressed genes (DEG) were considered as those associated with P < 0.05 and fold change ≥1.5 or <0.66. There were 124 DEG between females and males (91 up-regulated in females and 33 up-regulated in males). A total of 68% of the genes up-regulated in females were located in the X chromosome. Treatment with DKK1 resulted in 132 DEG in females (68 up-regulated and 64 down-regulated) and 136 DEG in males (90 up-regulated and 46 down-regulated). Of these, 34 genes were regulated by DKK1 in both sexes: 14 in the same direction and 20 in opposite directions. Analysis by Ingenuity® Pathway software indicated that changes in gene expression caused by DKK1 would increase formation of actin fibers in females and inhibit formation in males. DKK1 inhibited expression of AMOT in male embryos, indicating that DKK1 may inhibit Hippo signalling at this stage of development. Evidence for regulation of the PCP pathway by DKK1 was the finding that DKK1 regulated expression of genes involved in cell polarization and differentiation in both females and males. In both sexes, DKK1 regulated expression of many genes associated with HNF4A, a marker of hypoblast cells that promotes formation of cell junctions. In conclusion, female and male embryos developing in vitro have different transcriptomic profiles at the morula stage. DKK1 regulates cell differentiation and embryonic development in a sex-dependent manner and effects may be mediated, at least in part, by activation of the PCP pathway.Supported by USDA AFRI 2011-67015-30688 and NIH R03 HD080855.

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Kawao, Naoyuki, Hironobu Morita, Shunki Iemura, Masayoshi Ishida, and Hiroshi Kaji. "Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice." International Journal of Molecular Sciences 21, no. 7 (April 6, 2020): 2547. http://dx.doi.org/10.3390/ijms21072547.

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Mechanical unloading simultaneously induces muscle and bone loss, but its mechanisms are not fully understood. The interactions between skeletal muscle and bone have been recently noted. Although canonical wingless-related integration site (Wnt)/β-catenin signaling is crucial for bone metabolism, its roles in the muscle and bone interactions have remained unknown. Here, we performed comprehensive DNA microarray analyses to clarify humoral factors linking muscle to bone in response to mechanical unloading and hypergravity with 3 g in mice. We identified Dickkopf (Dkk) 2, a Wnt/β-catenin signaling inhibitor, as a gene whose expression was increased by hindlimb unloading (HU) and reduced by hypergravity in the soleus muscle of mice. HU significantly elevated serum Dkk2 levels and Dkk2 mRNA levels in the soleus muscle of mice whereas hypergravity significantly decreased those Dkk2 levels. In the simple regression analyses, serum Dkk2 levels were negatively and positively related to trabecular bone mineral density and mRNA levels of receptor activator of nuclear factor-kappa B ligand (RANKL) in the tibia of mice, respectively. Moreover, shear stress significantly suppressed Dkk2 mRNA levels in C2C12 cells, and cyclooxygenase inhibitors significantly antagonized the effects of shear stress on Dkk2 expression. On the other hand, Dkk2 suppressed the mRNA levels of osteogenic genes, alkaline phosphatase activity and mineralization, and it increased RANKL mRNA levels in mouse osteoblasts. In conclusion, we showed that muscle and serum Dkk2 levels are positively and negatively regulated during mechanical unloading and hypergravity in mice, respectively. An increase in Dkk2 expression in the skeletal muscle might contribute to disuse- and microgravity-induced bone and muscle loss.

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Kaiser, Martin, Maren Mieth, Peter Liebisch, Susanne Rötzer, Christian Jakob, Claudia Fleissner, Edgar Braendle, et al. "Serum Concentrations of DKK-1 Correlate with the Extent of Bone Disease in Multiple Myeloma." Blood 110, no. 11 (November 16, 2007): 3518. http://dx.doi.org/10.1182/blood.v110.11.3518.3518.

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Abstract Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells was reported to cause inhibition of osteoblast precursors. DKK-1 is an inhibitor of the Wnt/β-catenin signaling, which is a critical signaling pathway for the differentiation of mesenchymal stem cells into osteoblasts. So far there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. Methods: DKK-1 serum levels were quantified in 184 previously untreated MM patients and 33 MGUS patients by ELISA, using a monoclonal anti-DKK-1 antibody. For the evaluation of bone disease, skeletal X-rays were performed. Results: Serum DKK-1 was elevated in MM as compared to MGUS (mean 11,963 pg/mL versus 1993 pg/mL, P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL versus 15,209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL versus 17,915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: mean 3114 pg/mL vs. 3559 pg/mL vs. 24,068 pg/mL; P = 0.002). Conclusion: This is the largest study of DKK-1 serum levels in multiple myeloma patients and data show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, suggesting that DKK1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

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Safarnezhad Tameshkel, F., and M. H. Karbalaie Niya. "A new tool for breast cancer screening: Dickkopf-3 (DKK-3) biomarker potential." Breast 44 (March 2019): S91. http://dx.doi.org/10.1016/s0960-9776(19)30320-0.

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Ueno, Koji, Hiroshi Hirata, Shahana Majid, Yi Chen, Mohd S. Zaman, Z. Laura Tabatabai, Yuji Hinoda, and Rajvir Dahiya. "Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma." Molecular Carcinogenesis 50, no. 6 (January 25, 2011): 449–57. http://dx.doi.org/10.1002/mc.20729.

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Torigoe, Kenta, Kumiko Muta, Kiyokazu Tsuji, Ayuko Yamashita, Miki Torigoe, Shinichi Abe, Yuki Ota, Hiroshi Mukae, and Tomoya Nishino. "Association of Urinary Dickkopf-3 with Residual Renal Function Decline in Patients Undergoing Peritoneal Dialysis." Medicina 57, no. 6 (June 18, 2021): 631. http://dx.doi.org/10.3390/medicina57060631.

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Background and Objectives: Urinary levels of dickkopf-3 (DKK-3) are associated with poor renal survival in patients with non-dialytic chronic kidney disease. However, it remains unknown whether urinary DKK-3 levels can predict residual renal function (RRF) decline in patients undergoing peritoneal dialysis (PD). Therefore, we investigated the correlation between urinary levels of DKK-3 and the subsequent rate of RRF decline in PD patients. Materials and Methods: This study included 36 PD patients who underwent multiple peritoneal equivalent tests during 2011–2021. The relationship between baseline clinical characteristics and the subsequent annual rate of Kt/V decline was investigated. Results: The annual rate of renal Kt/V decline was 0.29 (range: 0.05–0.48), which correlated with renal Kt/V (r = 0.55, p = 0.0005) and 24 h urinary DKK-3 excretion (r = 0.61, p < 0.0001). Similarly, 24 h urinary DKK-3 excretion (β = 0.44, p = 0.0015) and renal Kt/V (β = 0.38, p = 0.0059) were independently associated with the annual rate of renal Kt/V decline in multivariate analyses. Conclusions: Urinary DKK-3 assessment may help identify PD patients at a high risk of RRF decline.

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Ning, Shujie, Yalin Wang, Xuejun Yuan, Shuying Wang, and Libo Huang. "Effect of autonomic nerves on Dickkopf-3 expression in the uterus during early pregnancy of rats." Animal Biology 65, no. 3-4 (2015): 241–55. http://dx.doi.org/10.1163/15707563-00002474.

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To explore how uterine innervations affect expression of Dickkopf-3 (DKK-3) during peri-implantation, we first examined the consequence of uterine neurectomy on embryo implantation events. We observed that amputation of autonomic nerves innervating the uterus led to the failure of on-time implantation in rats. We then analyzed the effect of neurectomy on expression of DKK-3 further using immunohistochemistry and quantitative real-time reverse transcription polymerase chain reaction. We observed that disconnection of autonomic nerve innervation significantly increased DKK-3 expression in the endometrium before and during invasion of the blastocyst. We also observed high levels of DKK-3 immunoreactivity in the vasculature of the uterus during peri-implantation. Thus, we speculate that DKK-3 may relate to implantation. Besides, our findings provide a new line of evidence that DKK-3 may be regulated by the autonomic nervous system.

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Hutterer, M., M. Medinger, G. Untergasser, K. Steinlechner, I. Gstrein, F. Deisenhammer, G. Stockhammer, and E. Gunsilius. "Dickkopf-3 (DKK-3) protein in cerebrospinal fluid (CSF): A biomarker for neoplastic meningitis?" Journal of Clinical Oncology 28, no. 15_suppl (May 20, 2010): e12517-e12517. http://dx.doi.org/10.1200/jco.2010.28.15_suppl.e12517.

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Zitt, Matthias, Gerold Untergasser, Albert Amberger, Patrizia Moser, Sylvia Stadlmann, Marion Zitt, Hannes M. Müller, et al. "Dickkopf-3 As a New Potential Marker for Neoangiogenesis in Colorectal Cancer: Expression in Cancer Tissue and Adjacent Non-Cancerous Tissue." Disease Markers 24, no. 2 (2008): 101–9. http://dx.doi.org/10.1155/2008/160907.

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Gene expression of Dickkopf-3 (Dkk-3) has been shown to be upregulated in tumor endothelium of colorectal cancer (CRC). For the first time, we analyzed Dkk-3 protein expression in CRC and its potential as a marker for neoangiogenesis. We used tissue microarrays (TMAs) to investigate Dkk-3 in microvessels of 403 CRC samples, 318 appropriate adjacent non-cancerous samples and 127 normal colorectal samples. Of cancer samples with CD31-positive microvessels, 67.7% were positive for Dkk-3. Dkk-3 staining was demonstrated in endothelial cells of all microvessels in nearly all cases. Dkk-3-positive samples showed a higher mean microvessel count than did Dkk-3-negative samples (P=0.001). Dkk-3 expression increased with rising numbers of microvessels per sample (P<0.0001). In adjacent samples with CD31-positive microvessels, 56% were Dkk-3-positive in all microvessels. Similar to cancer samples, Dkk-3-positive adjacent samples had a higher mean microvessel count than did Dkk-3-negative samples (P<0.0001), and Dkk-3 expression also increased with rising numbers of microvessels (P<0.0001). All microvessels in normal mucosa samples were negative for Dkk-3.Dkk-3 can be considered a putative pro-angiogenic protein in neovascularization and may possibly be a marker for neoangiogenesis in CRC. Further investigations will elucidate whether Dkk-3 is a target structure for novel therapies.

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Lin, Carol H., Yi Guo, Samia Ghaffar, Peter McQueen, Jonathan Pourmorady, Alexander Christ, Kevin Rooney, et al. "Dkk-3, a Secreted Wnt Antagonist, Suppresses Tumorigenic Potential and Pulmonary Metastasis in Osteosarcoma." Sarcoma 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/147541.

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Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades. Dickkopf-3 protein (Dkk-3/REIC) has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines. Usingin vivoandin vitrostudies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS. Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7%) compared to the control vector.In vitroexperiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector. Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS. Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma. Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.

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Kuo, Shu-Jui, Chao-Long Chen, Sung-Hsiung Chen, and Jih-Yang Ko. "Changes in Serum Bone Metabolism Markers after Living Donor Liver Transplantation (LDLT) and Their Association with Fracture Occurrences." Life 13, no. 7 (June 25, 2023): 1438. http://dx.doi.org/10.3390/life13071438.

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Living donor liver transplantation (LDLT) is lifesaving, but can lead to osteoporosis and fractures. In our 3-year study of 25 LDLT recipients, we observed significant reductions in lumbar spine and femoral neck T scores, along with bone resorption marker reductions and liver regeneration marker increases. Serum calcium levels increased, while osteoprotegerin (OPG) decreased and Dickkopf-related protein 1 (DKK-1) increased. Patients who suffered fractures within 3 years of LDLT had higher serum OPG, lower serum nuclear factor kappa B ligand (RANKL), a higher OPG/RANKL ratio and higher serum DKK-1 levels. OPG, RANKL, OPG/RANKL ratio and DKK-1 levels before LDLT predicted hip or spine fractures within three years after LDLT. Further research is necessary to determine the optimal level of osteoclastic activity for preventing fracture onset.

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