DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α,25-dihydroxyvitamin D3

Pendás-Franco, Natalia; García, José M.; Peña, Cristina; Valle, Noelia; Pálmer, Héctor G.; Heinäniemi, Merja; Carlberg, Carsten; Jiménez, Benilde; Bonilla, Félix; Múñoz, Alberto; González‐Sancho, José Manuel

doi:10.1038/onc.2008.88

Cited by 157 publications

(141 citation statements)

References 24 publications

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“…However, there was no significant difference in the mobility of AGS cells stably transfected with HSulf-1 and control cells. In accordance with these observations, we found that mRNA levels of metastasis-related genes, such as DKK1, MMP-2, S100A4, and S100P, (22,(28)(29)(30) were downregulated in HSulf-1 transfected MKN28 cells, but that there were no noticeable change in the expression of these genes in AGS cells (Fig. 2d).…”

Section: Resultssupporting

confidence: 85%

“…Of these genes, DKK4, S100A4, and S100P have been identified as Wnt signaling downstream target genes. (30) Although DKK4 is a Wnt antagonist, it is associated with the malignant properties of cancer cells. (29) However, another metastasis-related gene, namely MMP-2, was not a target of Wnt signaling, indicating possible regulation of multiple signaling pathways by HSulf-1 in the invasion of gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

Zhao

et al. 2011

Cancer Science

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The HSulf-1 gene encodes an extracellular 6-O-endosulfatase and regulates the sulfation status of heparan sulfate proteoglycans (HSPG). We have demonstrated that promoter hypermethylation is correlated with the HSulf-1 silencing in gastric cancer. To investigate the functional importance of HSulf-1 silencing in gastric cancer, we restored HSulf-1 expression in the gastric cancer cell line MKN28, which lacks endogenous HSulf-1. Following restoration of expression, HSulf-1 inhibited cell proliferation, motility, and invasion in vitro, as well as significantly suppressing the MKN28 xenograft model (P < 0.05). No noticeable changes in proliferation and motility were observed following restoration of HSulf-1 in another gastric cancer cell line, namely AGS cells. Interestingly, in MKN28 cells, which have been reported to be dependent on extracellular Wnt signaling, we found that HSulf-1 inhibited the transcriptional activity of the Wnt ⁄ b-catenin pathway and downregulated its targeted genes. Conversely, in AGS cells, in the constitutive Wnt ⁄ b-catenin pathway is active, HSulf-1 had no effect on the activity of the Wnt ⁄ b-catenin pathway. Furthermore, transfection of Wnt3a cDNA or b-catenin shRNA resulted in rescue or enhancement, respectively, of the effects of HSulf-1 in MKN28 cells. Furthermore, HSPG epitope analysis confirmed that HSulf-1 affected the structure of heparan sulfate on the cell surface. Together, the results of the present study suggest that extracellular HSulf-1 may function as a negative regulator of proliferation and invasion in gastric cancer by suppressing Wnt ⁄ b-catenin signaling at the cell surface. (Cancer Sci 2011; 102: 1815-1821 G astric cancer is the second most common cause of cancerrelated deaths worldwide.(1,2) Understanding the mechanisms involved in gastric tumorigenesis and metastasis is important for the development of new effective therapeutic agents.The HSulf-1 gene, characterized as Human ortholog of Qsulf-1, can hydrolyze the sulfate ester bonds of heparan sulfate proteoglycans (HSPG), leading to removal of the sulfate at the 6-O position of glucosamine. (3,4) It is believed that changes in the sulfation status of HSPG can affect their interactions with signaling molecules and therefore modulate signal transduction. (3,(5)(6)(7)(8)

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

Zhao

et al. 2011

Cancer Science

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“…Krieghoff et al (2006) reported that b-catenin localization in the cytoplasm and its subsequent translocation to the nucleus could be governed by competition between cytoplasmic and nuclear retention factors (for example, BCL9, APC, Axin and TCF4) for b-catenin. DKK4 also contains TCF-binding sites (Baehs et al, 2009) As a negative regulator and downstream target of Wnt/ b-catenin signalling, DKK4 like DKK1 provides a negative feedback loop that is important for regulating Wnt/b-catenin signalling in normal tissues (Krupnik et al, 1999;Pendas-Franco et al, 2008). Thus, loss of DKK4 expression in HCC may provide cancer cells with a growth advantage.…”

Section: Dkk4 -Cateninmentioning

confidence: 99%

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

et al. 2012

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Deregulation of Wnt/b-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of b-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/b-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in b-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated b-catenin responsive luciferase activity, and decreased both b-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n ¼ 8), reduction in tumour sizes was observed (P ¼ 0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with b-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of b-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC.

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“…While functioning upstream of the Wnt/β-catenin pathway, DKK1 and DKK4 are also downstream targets of the Wnt/β-catenin pathway, creating a negative feedback loop to regulate Wnt/β-catenin signalling [124,125] . However, this feedback mechanism is often abrogated in cancers including HCC [125,126] . Like DKK1 and DKK4, DKK2 also binds to LRP5/ LRP6 and Krms.…”

Section: Functions Of Dkks On the Wnt/β-catenin Pathwaymentioning

confidence: 99%

Dickkopfs and Wnt/β-catenin signalling in liver cancer

Fatima¹

2011

WJCO

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Liver cancer is the fifth and seventh most common cause of cancer in men and women, respectively. Wnt/β-catenin signalling has emerged as a critical player in both the development of normal liver as well as an oncogenic driver in hepatocellular carcinoma (HCC). Based on the current understanding, this article summarizes the possible mechanisms for the aberrant activation of this pathway with specific focus on HCC. Furthermore, we will discuss the role of dickkopfs (DKKs) in regulating Wnt/β-catenin signalling, which is poorly understood and understudied. DKKs are a family of secreted proteins that comprise at least four members, namely DKK1-DKK4, which act as inhibitors of Wnt/β-catenin signalling. Nevertheless, not all members antagonize Wnt/β-catenin signalling. Their functional significance in hepatocarcinogenesis remains to be further characterized for which these studies should provide new insights into the regulatory role of DKKs in Wnt/β-catenin signalling in hepatic carcinogenesis. Because of the important oncogenic roles, there are an increasing number of therapeutic molecules targeting β-catenin and the Wnt/ β-catenin pathway for potential therapy of HCC. hepatocellular carcinoma anD the unmet meDical neeDSLiver cancer ranks the fifth most common cancer in men and the second leading cause of cancer-related death. In women, it is the seventh most frequent cancer and sixth leading cause of cancer death [1] . Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver. Men are three times more likely to develop HCC than women and the incidence increases with age [2] . HCC is prevalent in Asia and Africa, but recently it is on the rise in the Western world due to an increase in hepatitis C virus (HCV) infection [3] . Risk factors for HCC include chronic hepatitis B virus (HBV) and HCV infections, cirrhosis, chronic alcohol abuse, aflatoxin ingestion, non-alcoholic steatohepatitis and other metabolic liver diseases [4,5] . Much of HCC occurs in the background of cirrhosis. About 80%-90% of patients with cirrhosis go on to develop HCC eventually and the remaining 10%-20% of cases develop HCC without cirrhosis. Furthermore, HBV and HCV infections increase the risk of developing cirrhosis and later HCC. Among the HCC

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DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α,25-dihydroxyvitamin D3

Cited by 157 publications

References 24 publications

HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

Dickkopfs and Wnt/β-catenin signalling in liver cancer

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