Dickkopf-related protein 2 induces G0/G1 arrest and apoptosis through suppressing Wnt/β-catenin signaling and is frequently methylated in breast cancer

Mu, Junhao; Hui, Tianli; Shao, Bianfei; Li, Lili; Du, Zhenfang; Lu, Liwei; Ye, Lin; Li, Shuman; Li, Qianqian; Xiao, Qian; Qiu, Zhu; Zhang, Yan; Fan, Jiangxia; Ren, Guosheng; Tao, Qian; Xiang, Tingxiu

doi:10.18632/oncotarget.17055

Cited by 27 publications

(20 citation statements)

References 40 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the whole, we comprehensively analyzed the expression profiles and prognostic value of DKKs in breast cancer subtypes. The main data indicated that a high DKK2 mRNA expression was associated with a better prognosis in breast cancer, which is consistent with the findings of a previous study ( 28 ). Nevertheless, we focused our attention on the clinical prognostic value of DKK2 in the normal-like subtype.…”

Section: Resultssupporting

confidence: 92%

Prognostic value of DKK2 from the Dickkopf family in human breast cancer

et al. 2018

View full text Add to dashboard Cite

Breast cancer is one of the most frequently diagnosed types of cancer with a high mortality and malignancy rate in women worldwide. The Dickkopf (DKK) protein family, as a canonical Wnt/β-catenin pathway antagonist, has been implicated in both physiological and pathological processes. This study aimed to comprehensively characterize the prognostic value and elucidate the mechanisms of DKKs in breast cancer and its subtypes. Firstly, DKK mRNA expression and corresponding outcome were analyzed by means of the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) platform based on PAM50 intrinsic breast cancer subtypes. Subsequently, we extracted breast cancer datasets from the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to validate the expression profile and prognostic values from the GOBO platform. Moreover, a protein-protein network was created and functional enrichment was conducted to explore the underlying mechanisms of action of the DKKs. In addition, we uncovered the genetic and epigenetic alterations of DKK2 in breast cancer. The main finding of this study was the differential roles of DKKs in the PAM50 subtypes of breast cancer analyzed. The overall trend was that a high level of DKK2 was associated with a good survival in breast cancer, although it played an opposite role in the Normal-like subtype. We also found that DKK2 carried out its functions through multiple signaling pathways, not limited to the Wnt/β-catenin cascade in breast cancer. Finally, we used our own data to validate the bioinformatics analysis data for DKK2 by RT-qPCR. Taken together, our findings suggest that DKK2 may be a potential prognostic biomarker for the Normal-like subtype of breast cancer. However, the prognostic role of DKKs in the subtypes of breast cancer still requires validation by larger sample studies in the future.

show abstract

Section: Resultssupporting

confidence: 92%

Prognostic value of DKK2 from the Dickkopf family in human breast cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Our results for patients after a primary resection are consistent with previous studies for gastric, colon, breast and hepatocellular carcinoma, where DKK2 was found as a tumor suppressor and its loss is associated with activation of the Wnt-pathway and consecutive tumor progression [19][20][21][22][23][24].…”

Section: Dkk2 Expression and Its Impact On Survivalsupporting

confidence: 91%

Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma

Schiffmann

Löser

Jacob

et al. 2020

Cancers

View full text Add to dashboard Cite

Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.

show abstract

“…Dickkopf-related protein 2 induces G0/G1 arrest and cell apoptosis by suppressing β-catenin activity in breast CSCs. 163 DACT1, a homolog of Dapper that is located at chromosomal region 14q23.1, promotes apoptosis in breast CSCs by antagonizing the Wnt/β-catenin signaling pathway. 164 Cadherin-11, a proapoptotic tumor suppressor, reduces the level of active phospho-β-catenin (ser552) to induce apoptosis in colorectal CSCs.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,233

998

View full text Add to dashboard Cite

Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

show abstract

Dickkopf-related protein 2 induces G0/G1 arrest and apoptosis through suppressing Wnt/β-catenin signaling and is frequently methylated in breast cancer

Cited by 27 publications

References 40 publications

Prognostic value of DKK2 from the Dickkopf family in human breast cancer

Prognostic value of DKK2 from the Dickkopf family in human breast cancer

Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma

Targeting cancer stem cell pathways for cancer therapy

Contact Info

Product

Resources

About