Elevated Levels of Dickkopf-1 Are Associated with β-Catenin Accumulation and Poor Prognosis in Patients with Chondrosarcoma

Chen, Changbao; Zhou, Hua; Zhang, Xiaolin; Ma, Xiaofang; Liu, Zhongjun; Liu, Xiaoguang

doi:10.1371/journal.pone.0105414

Cited by 28 publications

(29 citation statements)

References 35 publications

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“…In accordance with our survey, Chen et al (23) reported that both DKK-1 and b-catenin levels were in high level in chondrosarcoma when compared with nontumor tissues. Furthermore, DKK-1 and b-catenin levels were remarkably linked to overall survival.…”

Section: Discussionsupporting

confidence: 92%

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Diagnostic investigations of DKK‐1 and PDCD5 expression levels as independent prognostic markers of human chondrosarcoma

et al. 2016

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In this study, we investigated the expression levels of Dickkopf-1 (DKK-1) and programmed cell death 5 (PDCD5) by using quantitative real-time PCR and immunohistochemistry in patients with chondrosarcoma. The DKK-1 mRNA levels were significantly higher in chondrosarcoma when compared with the corresponding nontumor tissues (mean 6 SD: 4.23 6 1.54; 1.54 6 0.87; P 5 0.001). PDCD5 mRNA levels were remarkably deceased in tumor tissues when compared with corresponding nontumor tissues (mean 6 SD: 1.94 6 0.73; 5.42 6 1.73; P 5 0.001). The high and moderate DKK-1 expressions were observed for 60% of chondrosarcoma samples in comparison with 27.5% of corresponding nontumor tissues (P 5 0.001). Moreover, low expression of PDCD5 was found in 67.5% of the tumor tissues when compared with the nontumor tissues (32.5%; P 5 0.002). The results of this study showed that high DKK-1 expression levels were strongly related to MSTS stage (P 5 0.011) and the advancement of histological grade (P < 0.001). Furthermore, the PDCD5 expression levels were correlated with histological grade (P < 0.001), MSTS stage (P 5 0.016), and distant metastasis (P 5 0.001). Kaplan-Meier survival and log-rank survival showed that patients with high DKK-1 levels and low PDCD5 levels were correlated with shorter overall survival (log-rank test P < 0.001). PDCD5 levels, histological grade, and tumor stage were independent predictors of overall survival. In conclusion, DKK-1 and PDCD5 can be independent predictors of overall survival in patients suffering from chondrosarcoma.

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Section: Discussionsupporting

confidence: 92%

“…Furthermore, DKK‐1 and β‐catenin levels were remarkably linked to overall survival. The association of increased DKK‐1 levels with β‐catenin accumulation has been indicated in chondrosarcoma, and its expression was correlated with poor prognosis in patients with chondrosarcoma .…”

Section: Discussionmentioning

confidence: 98%

Diagnostic investigations of DKK‐1 and PDCD5 expression levels as independent prognostic markers of human chondrosarcoma

et al. 2016

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“…Detailed experimental procedures for immunohistochemistry have been described previously. [29][30][31] Briefly, after antigen retrieval, PRMT1 (ab73246; 1:200; Abcam) and YAP (ab39361; 1:100; Abcam) immunoreactivities were detected using the EnVision+, Peroxidase system (DAKO Diagnostics, Glostrup, Denmark). The slides were developed with DAB (diaminobenzidine) substrate (DAKO Diagnostics) and counterstained with hematoxylin.…”

Section: Immunohistochemistry and Evaluation Of Stainingmentioning

confidence: 99%

PRMT1 potentiates chondrosarcoma development through activation of YAP activity

Chen

Zhou

Zhang

et al. 2019

Molecular Carcinogenesis

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Protein arginine methyltransferase 1 (PRMT1) is identified as an oncogene implicated in various types of human cancers, while Yes‐associated protein (YAP) as a key transcriptional coactivator of the Hippo signaling plays a vital role in tissue homeostasis and tumorigenesis. To date, the underlying biological functions, prognostic values, and potential mechanisms of PRMT1 and YAP in chondrosarcoma development have not been clearly elucidated. Here, we show that upregulation of PRMT1 and YAP is significantly detected in human chondrosarcoma specimens. Elevated levels of PRMT1 positively correlated with YAP nuclear accumulation are significantly associated with high‐grade chondrosarcoma and poor prognosis. Moreover, YAP is recognized as an independent prognostic factor for chondrosarcoma patients. Ectopic expression of PRMT1 potentiates, but depletion of PRMT1 attenuates, chondrosarcoma cell growth in vitro and in vivo. Mechanistically, we have discovered that PRMT1 functions upstream of LATS1 and suppresses LATS1‐mediated phosphorylation of YAP (Ser127), and thus promotes chondrosarcoma cell survival in a YAP‐dependent manner. Collectively, our study identifies PRMT1 as a positive regulator of YAP activity in chondrosarcoma, highlighting a novel therapeutic target against chondrosarcoma and other YAP‐driven cancers.

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“…In support of this, DKK1 positivity has been associated with lymph node metastasis in cancers (Kemik et al , ; Li et al , ; Shi et al , ; Shi et al , ; ). DKK1 staining in tumours has also been co‐detected with β‐catenin, and in some instances, patients with dual staining had a worse prognosis, including decreased overall survival (Yu et al , ; Xu et al , ; Chen et al , , ; Shi et al , , ). It is puzzling that DKK1, an inhibitor of β‐catenin‐dependent Wnt signalling, is detected in tumours with β‐catenin, an indicator of activated Wnt/β‐catenin signalling.…”

Section: Dkk1 Overexpression In Cancermentioning

confidence: 99%

Rationale for targeting the Wnt signalling modulator Dickkopf‐1 for oncology

Kagey¹,

2017

British J Pharmacology

100

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Wnt signalling is a fundamental pathway involved in embryonic development and adult tissue homeostasis. Mutations in the pathway frequently lead to developmental defects and cancer. As such, therapeutic intervention of this pathway has generated tremendous interest. Dickkopf‐1 (DKK1) is a secreted inhibitor of β‐catenin‐dependent Wnt signalling and was originally characterized as a tumour suppressor based on the prevailing view that Wnt signalling promotes cancer pathogenesis. However, DKK1 appears to increase tumour growth and metastasis in preclinical models and its elevated expression correlates with a poor prognosis in a range of cancers, indicating that DKK1 has more complex cellular and biological functions than originally appreciated. Here, we review current evidence for the cancer‐promoting activity of DKK1 and recent insights into the effects of DKK1 on signalling pathways in both cancer and immune cells. We discuss the rationale and promise of targeting DKK1 for oncology.Linked ArticlesThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc

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Elevated Levels of Dickkopf-1 Are Associated with β-Catenin Accumulation and Poor Prognosis in Patients with Chondrosarcoma

Cited by 28 publications

References 35 publications

Diagnostic investigations of DKK‐1 and PDCD5 expression levels as independent prognostic markers of human chondrosarcoma

Diagnostic investigations of DKK‐1 and PDCD5 expression levels as independent prognostic markers of human chondrosarcoma

PRMT1 potentiates chondrosarcoma development through activation of YAP activity

Rationale for targeting the Wnt signalling modulator Dickkopf‐1 for oncology

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