Reduced expression of REIC/Dkk-3 gene in non-small cell lung cancer

Nozaki, Isao; Tsuji, Toshiya; Iijima, O; Ohmura, Yasushi; Andou, Akio; Miyazaki, Masaru; Shimizu, Nobuaki; Namba, Masayoshi

doi:10.3892/ijo.19.1.117

Cited by 75 publications

(77 citation statements)

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“…Dkk-3 is downregulated in various type of cancer, including non-small-cell lung carcinoma (Tsuji et al, 2000;Nozaki et al, 2001), acute lymphoblastic leukemia (Roman-Gomez et al, 2004a) hepatocellular carcinoma (Hsieh et al, 2004), and renal cell carcinoma (Kurose et al, 2004). Although the Dkk-3 gene is localized on chromosome 11p15 where loss of heterozygocity in human cancers is often observed (Tsuji et al, 2000), several lines of evidence have shown that Dkk-3 downregulation in cancers is owing to promoter hypermethylation (Kobayashi et al, 2002;Lodygin et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Regulation of prostate cell growth and morphogenesis by Dickkopf-3

et al. 2006

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Wnt signalling plays a critical role in the development of cancer. Recent studies indicate that Wnt signalling is negatively regulated by secreted Wnt antagonists such as secreted frizzled related proteins (sFRPs) and Dickkopfs (Dkks). We compared Dkk family expression levels in normal prostate and prostate cancer cells and found a reduction in Dkk-3 expression in cancer cells. Ectopic expression of Dkk-3 inhibited colony formation in LNCaP and PC3 prostate cancer cell lines and inducible expression of Dkk-3 reduced LNCaP cell proliferation. Moreover, small interfering RNAmediated downregulation of Dkk-3 enhanced cell cycle progression in untransformed RWPE-1 prostate epithelial cells. Immunohistochemical analysis revealed that Dkk-3 is expressed in a subset of normal prostate gland acini and that Dkk-3 expression is reduced in prostate tumours, particularly those with a high Gleason grade, suggesting a role for Dkk-3 in postmitotic differentiation. Consistent with this, depletion of Dkk-3 disrupted acinar morphogenesis of RWPE-1 cells in a threedimensional cell culture model. Our results are consistent with the loss of Dkk-3 expression resulting in impairment of glandular structure and uncontrolled prostate epithelial cell (PrEC) proliferation, both of which are crucial for prostate cancer progression.

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Section: Discussionmentioning

confidence: 99%

Regulation of prostate cell growth and morphogenesis by Dickkopf-3

et al. 2006

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“…DKKs, especially DKK-1 and -3, have been implicated in tumorigenesis. Although most authors focused on down-regulation of DKK expression in various cancer models and tissues (5,14,36,37), the role of DKKs for invasion has scarcely been investigated. Hoang et al (38) described an inhibitory effect of DKK-3 on invasion and motility of osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines

Pukrop

Klemm

Hagemann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

323

290

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Interactions between neoplastic and stromal cells contribute to tumor progression. Wnt genes, involved in cell migration and often deregulated in cancers, are attractive candidates to regulate these effects. We have recently shown that coculture of breast cancer cells with macrophages enhances invasiveness via matrix metalloproteases and TNF-␣. Here we demonstrate that coculture of MCF-7 cells and macrophages leads to up-regulation of Wnt 5a in the latter. This was accompanied by activation of AP-1͞c-Jun in MCF-7. Recombinant Wnt 5a mimicked the coculture effect. Wnt 5a was also detectable in tumor-associated macrophages in primary breast cancers. Experiments with agonists and antagonists of Wnt signaling revealed that a functional canonical pathway in the tumor cells was a necessary prerequisite; however, noncanonical signaling via Wnt 5a and the Jun-N-terminal kinase pathway was critical for invasiveness. It was also responsible for induction of matrix metalloprotease-7, known to release TNF-␣. All these effects could be antagonized by dickkopf-1. Our results indicate that Wnt 5a is essential for macrophage-induced invasiveness, because it regulates tumor cell migration as well as proteolytic activity of the macrophages. The function of Wnt 5a as either a suppressor or promoter of malignant progression seems to be modulated by intercellular interactions. Wnt 5a detection in tumor-associated macrophages in breast cancer biopsies supports the assumption that similar events play a role in vivo.tumor microenvironment ͉ TNF-␣ ͉ matrix metalloproteases

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“…Krm2 can function as a switch that changes Dkk-2 from an activator to an inhibitor of Wnt/LRP6 signaling [11] . Dkk-3/REIC gene (chromosome 11p15.2) expression level was reported to be decreased in non-small cell lung cancer [12,13] , renal clear cell carcinoma, urinary bladder cancer, prostate cancer, pancreatic carcinoma, hepatoma, malignant melanoma, and acute lymphocytic leukemia (ALL) [9,[14][15][16] . Dkk-3 methylation occurred at an early stage in ALL pathogenesis and also influenced the prognosis [15] .…”

Section: Introductionmentioning

confidence: 99%

Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer

Maehata¹,

Taniguchi²,

Yamamoto³

et al. 2008

WJG

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AIM:To clarify alterations of Dickkopfs (Dkks) and Kremen2 (Krm2) in gastrointestinal cancer. METHODS:We investigated the expression profiles and epigenetic alterations of Dkks and Krm2 genes in gastrointestinal cancer using RT-PCR, tissue microarray analysis, and methylation specific PCR (MSP). Cancer cells were treated with the demethylating agent and/or histone deacetylase inhibitor. WST-8 assays and in vitro invasion assays after treatment with specific siRNA for those genes were performed. RESULTS:Dkks and Krm2 expression levels were reduced in a certain subset of the gastrointestinal cancer cell lines and cancer tissues. This was correlated with promoter hypermethylation. There were significant correlations between Dkks over-expression levels and beta-catenin over-expression in colorectal cancer. In colorectal cancers with beta-catenin over-expression, Dkk-1 expression levels were significantly lower in those with lymph node metastases than in those without. Down-regulation of Dkks expression by siRNA resulted in a significant increase in cancer cell growth and invasiveness in vitro .CONCLUSION: Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis.

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Reduced expression of REIC/Dkk-3 gene in non-small cell lung cancer

Cited by 75 publications

References 0 publications

Regulation of prostate cell growth and morphogenesis by Dickkopf-3

Regulation of prostate cell growth and morphogenesis by Dickkopf-3

Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines

Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer

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