Dickkopf-3 in Human Malignant Tumours: A Clinical Viewpoint

Lee, Eun‐Ju; Nguyen, Que Thanh Thanh; Lee, Moo-Yul

doi:10.21873/anticanres.14617

Cited by 11 publications

(9 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the numerous regulators of the classical Wnt pathway, β-catenin is a key factor, while dKK3 is a downstream inhibitor of the Wnt pathway. In malignant tumor cells, dKK3 was associated with the induction of apoptosis and inhibition of invasion by regulating β-catenin signaling, and c-Jun N-terminal kinase-dependent cellular pathways, as reported by Lee et al (17). It has been reported that β-catenin may be a central molecule mediating osteoblast viability and differentiation (41).…”

Section: Discussionmentioning

confidence: 58%

“…It has been reported that β-catenin may be a central molecule mediating osteoblast viability and differentiation ( 41 ). In addition, DKK3 inhibited the Wnt signaling pathway by hydrolyzing β-catenin/APC/GSK3β, thereby inhibiting the entry of β-catenin into the nucleus for transcription ( 17 ). Therefore, in OA, DKK3 degrades β-catenin via ubiquitination, thereby degrading the downstream signaling pathway factors of β-catenin and inhibiting nuclear transcription of the Wnt pathway ( 15 ), delaying abnormal remodeling of subchondral bone.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the mechanisms of action of DKK3 differ from those of other proteins in the DDK gene family. Lee et al ( 17 ) demonstrated that DKK3 attenuated β-catenin protein expression and its transcriptional activity via the interaction with β-transducin repeat-containing protein (β-TrCP) and prevented the translocation of β-catenin to the nucleus. DKK3 expression levels in the subchondral bone, as well as its role in osteocyte formation have not yet been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis

et al. 2022

View full text Add to dashboard Cite

Osteoarthritis (OA) is condition which poses a main concern to the aging population and its severity is expected to increase with the increasing life expectancy. In the future, several possible targets for OA treatment need to be defined. dickkopf-related protein 3 (dKK3) is an atypical member of the Wnt-antagonistic dickkopf-related protein (dKK) family. The availability of research into the role of dKK3 in the abnormal remodeling of subchondral bone in human knee joints is currently limited. Thus, the aim of the present study was the evaluation of dKK3 expression in the abnormal bone remodeling of subchondral bone in human knee OA in order to clarify the role of dKK3 in subchondral bone remodeling and to acknowledge its potential relevance to β-catenin. In total, 38 specimens were collected from osteotomies of the medial tibial plateau of the human knee. The patient samples were then divided into the normal, mild, moderate and severe symptom groups, according to the Osteoarthritis Research Society International (OARSI) score. Following hematoxylin and eosin (H&E) and Safranin O-fast green staining for alkaline phosphatase (AZO method), changes in the distribution and number of osteocytes in the subchondral bone and the degree of sclerosis of the subchondral bone were observed. Immunohistochemical staining, immunofluorescence, western blot analysis and reverse-transcription quantitative PcR (RT-qPcR) were used for the detection of dKK3 and β-catenin expression level changes in osteoblasts in the subchondral bone of the medial tibial plateau. H&E and alkaline phosphatase staining revealed that the total number of osteocytes in the subchondral bone increased with the severity of the disease. The samples were also evaluated using Safranin O-Fast Green staining and were attributed a score according to the OARSI scoring system: The scoring number and cartilage damage increased along with OA severity. Immunohistochemistry and immunofluorescence assays demonstrated that β-catenin expression in osteocytes increased from mild to moderate, whereas dKK3 expression decreased with the development of arthritis from normal, mild to moderate. According to the results of western blot analysis, β-catenin expression was higher in moderate OA and then decreased in severe OA. On the other hand, the dKK3 levels decreased along with the progression from normal, mild to moderate OA. The results of RT-qPcR demonstrated that β-catenin and dKK3 gene expression differed with the degree of OA. On the whole, the present study demonstrates that dKK3 and β-catenin may play opposite roles in OA subchondral bone remodeling.

show abstract

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Another study showed that it could inhibit cardiomyocyte hypertrophy by targeting HAND2 ( 54 ). DKK3 is a member of the Dickkopf family, which is decreased in a variety of cancers serving as a tumor suppressor gene ( 55 ). In ApoE-deficient mice, the expression of DKK3 was involved in the pathogenesis of atherosclerosis via the Wnt/β-catenin pathway ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

The Integrative Analysis of Competitive Endogenous RNA Regulatory Networks in Coronary Artery Disease

Yan

Zhu

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Background: Coronary artery disease (CAD) is the leading cause of cardiovascular death. The competitive endogenous RNAs (ceRNAs) hypothesis is a new theory that explains the relationship between lncRNAs and miRNAs. The mechanism of ceRNAs in the pathological process of CAD has not been fully elucidated. The objective of this study was to explore the ceRNA mechanism in CAD using the integrative bioinformatics analysis and provide new research ideas for the occurrence and development of CAD.Methods: The GSE113079 dataset was downloaded, and differentially expressed lncRNAs (DElncRNAs) and genes (DEGs) were identified using the limma package in the R language. Weighted gene correlation network analysis (WGCNA) was performed on DElncRNAs and DEGs to explore lncRNAs and genes associated with CAD. Functional enrichment analysis was performed on hub genes in the significant module identified via WGCNA. Four online databases, including TargetScan, miRDB, miRTarBase, and Starbase, combined with an online tool, miRWalk, were used to construct ceRNA regulatory networks.Results: DEGs were clustered into ten co-expression modules with different colors using WGCNA. The brown module was identified as the key module with the highest correlation coefficient. 188 hub genes were identified in the brown module for functional enrichment analysis. DElncRNAs were clustered into sixteen modules, including seven modules related to CAD with the correlation coefficient more than 0.5. Three ceRNA networks were identified, including OIP5-AS1-miR-204-5p/miR-211-5p-SMOC1, OIP5-AS1-miR-92b-3p-DKK3, and OIP5-AS1-miR-25-3p-TMEM184B.Conclusion: Three ceRNA regulatory networks identified in this study may play crucial roles in the occurrence and development of CAD, which provide novel insights into the ceRNA mechanism in CAD.

show abstract

“…Dickkopf-3 (DKK3) is considered a tumor suppressor as it is often deleted in cancers [ 4 , 5 ] and is frequently downregulated owing to epigenetic inactivation in cervical, lung, prostate, bladder, gallbladder, and breast cancers [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. In addition, a significant relationship between aberrantly reduced DKK3 expression and poor prognosis was reported in uterine, cervical, colorectal, and pancreatic cancers [ 10 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

Park

Lee

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Dickkopf-3 in Human Malignant Tumours: A Clinical Viewpoint

Cited by 11 publications

References 87 publications

Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis

Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis

The Integrative Analysis of Competitive Endogenous RNA Regulatory Networks in Coronary Artery Disease

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

Contact Info

Product

Resources

About