Dickkopf‐1 expression is down‐regulated during the colorectal adenoma–carcinoma sequence and correlates with reduced microvessel density and <scp>VEGF</scp> expression

Li, Yong; Sun, Bei; Qi, Lisha; Li, Yixian; Zhao, Xiulan; Zhang, Danfang; Zhang, Yanhui

doi:10.1111/his.12474

Cited by 41 publications

(37 citation statements)

References 33 publications

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“…This suggests that the WNT/␤-catenin-mediated metabolic reprogramming of cancer cells can directly affect vessel density in tumors. In fact, in other models, canonical WNT signaling has been strongly linked to tumor angiogenesis by directly regulating the expression of the proangiogenic growth factor (GF) vascular endothelial GF (56)(57)(58). Since blood vessels deliver nutrients and O 2 to tissues, it is hardly surprising that metabolism and angiogenesis should be coregulated by WNT signaling.…”

Section: Canonical Wnt Signaling and Cancer Cell Metabolismmentioning

confidence: 99%

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

Sherwood

2015

Molecular and Cellular Biology

129

105

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WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.

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Section: Canonical Wnt Signaling and Cancer Cell Metabolismmentioning

confidence: 99%

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

Sherwood

2015

Molecular and Cellular Biology

129

105

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“…DKK-1 is downregulated in a number of tumors, of which colon cancer is the most paradigmatic. We and others have reported reduced expression of DKK-1 in colon cancer [11,42] that in a proportion of cases is associated with promoter hypermethylation [20,43,44] . This was an unexpected finding because as a β-catenin/TCF target DKK-1 gene was predicted to be upregulated in a malignancy characterized by a constitutively hyperactivated Wnt/β-catenin pathway.…”

Section: Research Highlightmentioning

confidence: 66%

“…Supporting these data, analysis of DKK-1 expression in human colon tumors demonstrated an inverse correlation with tumor grade, presence of metastasis, and recurrence [45] . Moreover, downregulation of DKK-1 expression is concomitant with reduced epithelial-to-mesenchymal transition (EMT) phenotype [45] , and with reduced angiogenesis and VEGF expression [42] . The complex behavior of DKK-1 as a tumor suppressor or metastasis promoter may rely on the diverse and sometimes opposite actions of Wnt/β-catenin signaling in different tissues, together with other Wnt-independent effects that may add to the array of DKK-1 actions.…”

Section: Research Highlightmentioning

confidence: 99%

The complex life of DICKKOPF-1 in cancer cells

González‐Sancho¹,

Rojo²,

Múñoz

2015

Can Cell Microenviron

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The role of DICKKOPF (DKK)-1 in human cancer is controversial. DKK-1 behaves as an inhibitor of the canonical Wnt/-catenin signaling pathway acting at the plasma membrane, although several studies have proposed effects that are independent of the inhibition of -catenin transcriptional activity, in some cases mediated by the activation of c-Jun N-terminal kinase (JNK). Recently, a proportion of DKK-1 protein has been found within the nucleus of human intestinal epithelial cells following an apical-to-basal crypt decreasing gradient, and in that of colon carcinoma cells. Moreover, we show here that in the human mammary gland DKK-1 is also present within the nucleus of many differentiated luminal epithelial cells and in that of a small proportion of myoepithelial cells. Nuclear DKK-1 binds to actively transcribed chromatin and regulates the expression of specific genes, some of which are involved in cell proliferation, survival and stemness, and in the defense against xenobiotics. This may explain the finding that while DKK-1 is downregulated more rapidly in the nucleus than in the cytosol during colon carcinoma progression, its expression remains high in a percentage of patients who do not respond to chemotherapy. Available data suggest that the accumulation of DKK-1 in the nucleus of colon carcinoma cells depends on signals from the surrounding tumor microenvironment.

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“…On the other hand, the expression pattern of Dkk-1, an inhibitor of Wnt/b-catenin pathway, by blocking Wnt signaling receptor complexes and contributing to colon cancer suppression, is remarkably downregulated in the colonic biopsies of colorectal cancer patients, and its downregulation is disclosed as a biomarker of chemoresistance and poor clinical outcome (25)(26)(27)(28)(29). Although the overall available data still have discrepancies, Dkk-1 has been found to not only act as an inhibitor of Wnt/ b-catenin signaling but also has additional b-catenin-independent tumor suppressor, antiangiogenesis, and antimetastasis actions in colorectal cancer disease (27,41). Likewise, CDNK-1A, a tumor suppressor gene encoding a potent cell-cycle inhibitory factor (CDKN1A, p21, or CIP1), is downregulated or even lost in most colorectal cancer cases (30), and some colorectal cancer patients have anti-CDKN1A autoantibodies in their colorectal tissues (31).…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, CDNK-1A, a tumor suppressor gene encoding a potent cell-cycle inhibitory factor (CDKN1A, p21, or CIP1), is downregulated or even lost in most colorectal cancer cases (30), and some colorectal cancer patients have anti-CDKN1A autoantibodies in their colorectal tissues (31). On the basis of these facts, it is conceivable that targeting these crucial colorectal tumorigenesis pathways, through repression of Wnt/b-catenin activity and/or stimulation of Dkk-1 and CDNK-1A, may hold tremendous therapeutic potential in treating colorectal cancer and other cancers, and in enhancing the cytotoxic effects of chemotherapeutic agents (25,41). Interestingly, data of the current study are in agreement and showed that cotherapy with paricalcitol and 5-FU significantly interacted to repress the overexpressed Wnt and b-catenin, and upregulated the decreased Dkk-1 and CDNK-1A in the colorectal tissues of the chemically induced colorectal cancer model, suggesting a cooperative mechanism between the two drugs that, in part, might be behind their observed tumoricidal effect.…”

Section: Discussionmentioning

confidence: 99%

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

El-Shemi

Refaat

Kensara

et al. 2016

Cancer Prevention Research

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Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), whereas paricalcitol (2.5 mg/kg/day; 3 days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, b-catenin, DKK-1, CDNK-1A, NF-kB, and COX-2 genes, and ELISA was used to quantify the protein levels of b-catenin, COX-2, HSP90, and VEGF. IHC was additionally used to measure b-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, b-catenin, NF-kB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. Ó2016 AACR.

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Dickkopf‐1 expression is down‐regulated during the colorectal adenoma–carcinoma sequence and correlates with reduced microvessel density and VEGF expression

Abstract: This study is the first to show the roles of Dkk1 during the colorectal adenoma-carcinoma sequence, which may involve suppression of the tumorigenesis and angiogenesis of CRC. Dkk1 could therefore serve as a potential target for tumour therapy.

Cited by 41 publications

References 33 publications

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

The complex life of DICKKOPF-1 in cancer cells

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

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