DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway

Niida, Atsushi; Hiroko, Takatoshi; Kasai, Mana; Furukawa, Yoichi; Nakamura, Yusuke; Suzuki, Yutaka; Sugano, Sumio; Akiyama, Tetsu

doi:10.1038/sj.onc.1207892

Cited by 511 publications

(392 citation statements)

References 30 publications

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“…Our data show that Dkk3 expression is further suppressed in NSCLC cell lines with chemoresistance obtained by chronic cisplatin exposure, however the manner in which Dkk3 is reduced is unclear. One possible explanation is the feedback modulating the Wnt/β-catenin pathway, i.e., the Wnt/β-catenin pathway is activated in cisplatin resistance and, activation of Wnt/β-catenin signaling in turn reduces DKK1 expression (25). It is unknown whether DKK3 expression is also negatively regulated by Wnt/β-catenin signaling, however the determinant mechanism should be investigated (10).…”

Section: Discussionmentioning

confidence: 99%

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Wang

et al. 2014

Oncology Reports

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Abstract. Previous studies have shown that is inactivated in lung cancer cells, while the inactivation of the Wnt/β-catenin signaling pathway by Dkk3 inhibits lung cancer progression. In the present study, we investigated whether Dkk3 enhances the sensitivity of lung cancer cells to cisplatin. A549, Calu1 and H460 lung adenocarcinoma cell lines were transfected with DKK3 siRNA, while the cisplatin-resistant subline A549cis was transfected with DKK3. DKK3 expression was attenuated in A549cis, Calu1cis and H460cis compared to A549, Calu1 and H460, respectively. Lung adenocarcinoma cell growth, proliferation, apoptosis, cell cycle in vitro and in vivo were then analyzed. DKK3 knockdown by siRNA transfection rendered A549, Calu1 and H460 resistant to cisplatin. As a result of DKK3 transfection, the expression of DKK3 and E-cadherin was significantly upregulated, while that of MMP7, survivin, c-myc and cyclin D1 was downregulated. DKK3 overexpression retarded cell proliferation, induced cell cycle arrest and apoptosis, and reduced cell invasive ability in the A549 and A549cis cells. In addition, the proportions of apoptotic cells and the PARP level were significantly increased in A549cis-and H460cis-DKK3 cells treated with cisplatin. Moreover, tumor growth was retarded more in cisplatin-treated nude mice seeded with A549cis-DKK3 cells than with A549cis cells. Cell viability increased with the pretreatment of SB216763 for 2 h in A549cis and A549cis-DKK3 cells incubated with cisplatin (1 µM) for 72 h. In conclusion, the re-activation of Dkk3 enhances the chemosensitivity to cisplatin in cisplatin-resistant lung adenocarcinoma cell lines, which requires additional studies to realize this potential in clinical use. IntroductionLung cancer has emerged as the third leading cause of cancer-related mortality worldwide (1). In the USA, over 200,000 new lung cancer cases are diagnosed annually, causing over 150,000 deaths in one year (1). Approximately 85% of lung cancer patients suffer from non-small cell lung cancer (NSCLC). Due to the comparative therapeutic advantage, cisplatin-based combination regimens are recommended as the optimal choice currently for the majority of NSCLC patients indicative of chemotherapy or adjuvant chemotherapy (2). However, the average survival time for patients with advanced stage of NSCLC receiving cisplatin plus gemcitabine treatment is ~16 months and may even be reduced to 12 months in those with cisplatin-resistance (3). The dilemma in managing late-stage NSCLC requires the elucidation of the mechanisms in cisplatin resistance to define novel, effective and applicable therapeutic targets for lung cancer (2,3).Several signal transduction pathways controlling chemosensitivity are aberrantly activated in various types of cancer, among which Wnt is of special significance (4). The role of Wnt1/Int-1 in the induction of mouse mammary tumor as an integration site for mouse mammary tumor virus (MMTV) was first recognized 30 years ago (4). Wnt/β-catenin signaling is initiated by the binding of secre...

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Section: Discussionmentioning

confidence: 99%

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Wang

et al. 2014

Oncology Reports

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“…Given that the Wnt signaling cascade with its antagonist Dkk-1 has been proposed to have crucial roles for maintaining homeostasis of a variety of tissues including the skin, 27 and that the physiologic Dkk-1 level is of vital importance to maintaining its biological functions, 28 we speculate that curcumin could precisely control the Dkk-1 level in a temporospatial manner to regulate the downstream Wnt signaling pathway, as Dkk-1 has been shown to participate in a negative feedback loop in Wnt signaling as well. 29 However, more studies are required to fully elucidate its less well-understood role in wound healing.…”

Section: Discussionmentioning

confidence: 99%

Nano-formulated curcumin accelerates acute wound healing through Dkk-1-mediated fibroblast mobilization and MCP-1-mediated anti-inflammation

et al. 2017

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Turmeric, a product of Curcuma longa, has a very long history of being used for the treatment of wounds in many Asian countries. Curcumin, the principal curcuminoid of turmeric, has recently been identified as a main mediator of turmeric's medicinal properties. However, the inherent limitations of the compound itself, such as hydrophobicity, instability, poor absorption and rapid systemic elimination, pose big hurdles for translation to wider clinical application. We present here an approach for engineering curcumin/gelatin-blended nanofibrous mats (NMs) by electrospinning to adequately enhance the bioavailability of the hydrophobic curcumin for wound repair. Curcumin was successfully formulated as an amorphous nanosolid dispersion and favorably released from gelatin-based biomimetic NMs that could be easily applied topically to experimental wounds. We show synergistic signaling by the released curcumin during the healing process: (i) mobilization of wound site fibroblasts by activating the Wnt signaling pathway, partly mediated through Dickkopf-related protein-1, and (ii) persistent inhibition of the inflammatory response through decreased expression of monocyte chemoattractant protein-1 by fibroblasts. With a combination of these effects, the curcumin/gelatin-blended NMs enhanced the regenerative process in a rat model of acute wounds, providing a method for translating this ancient medicine for use in modern wound therapy.

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“…26,32,41,49 DKK1 binding to LRP6 may also decrease Wnt/β-catenin signaling map analysis of gene similarities and segregation between control skin and lung MPCs; yellow and red indicate high and low levels of expression, respectively. M-O, Probes belonging to gene ontology functional categories were selected from the whole expression data of the lung and skin MPC groups, and corresponding heat maps of expression data were constructed.…”

Section: Discussionmentioning

confidence: 99%

“…BMPR signaling through SMADs 1/5/8 has been shown to regulate transcription of Dkk1 during patterning in development. [41][42][43][44][45][46] PDK4 can also directly phosphorylate SMADs 1/5/8 and regulate their activity. 47 Because deregulated or reduced BMP signaling is a common feature of PAH, 8,48 it is not surprising that the gene expression trends would be similar in the skin MCs from BMPR2-mutant, CAV1-mutant, and IPAH patients.…”

Section: Discussionmentioning

confidence: 99%

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

et al. 2016

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Rapid access to lung-derived cells from stable subjects is a major challenge in the pulmonary hypertension field, given the relative contraindication of lung biopsy. In these studies, we sought to demonstrate the importance of evaluating a cell type that actively participates in disease processes, as well as the potential to translate these findings to vascular beds in other nonlung tissues, in this instance perivascular skin mesenchymal cells (MCs). We utilized posttransplant or autopsy lung explant-derived cells (ABCG2-expressing mesenchymal progenitor cells [MPCs], fibroblasts) and skin-derived MCs to test the hypothesis that perivascular ABCG2 MPCs derived from pulmonary arterial hypertension (PAH) patient lung and skin would express a gene profile reflective of ongoing vascular dysfunction. By analyzing the genetic signatures and pathways associated with abnormal ABCG2 lung MPC phenotypes during PAH and evaluating them in lung-and skinderived MCs, we have identified potential predictor genes for detection of PAH as well as a targetable mechanism to restore MPCs and microvascular function. These studies are the first to explore the utility of expanding the study of ABCG2 MPC regulation of the pulmonary microvasculature to the epidermis, in order to identify potential markers for adult lung vascular disease, such as PAH.Keywords: mesenchymal progenitor cells, skin, lung, microvascular, pulmonary hypertension, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, BMPR2, Wnt signaling, LRP6, DKK1. Pulmonary vascular dysfunction or disease (PVD) is characterized by altered lung vascular structure and function. A significant loss of vascular-bed function, as seen in PVD, is thought to precede the clinical presentation of pulmonary hypertension (PH). 1 PH is associated with a wide array of comorbid conditions, such as systemic sclerosis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, and also occurs as a primary PVD known as either idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (HPAH). 2-4 PH is characterized by elevated pulmonary artery pressures and widespread vascular remodeling, including endothelial cell dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. 5-7 All forms of PH have a high mortality rate despite current therapeutic options. The current limited understanding of PVD as a predecessor to PH and lack of diagnostic approaches or criteria specific to preclinical PVD have hampered the study of the early stages of PVD in both rodent models and the clinical setting.Approximately 80% of HPAH patients have a known mutation in the gene bone morphogenetic protein receptor type 2 (BMPR2). BMPR2 mutation-associated PAH is an autosomal dominant disease with low penetrance (approx. 20%); hence, not all mutation carriers develop PAH. In addition, approximately 20% of patients initially labeled as having IPAH also have a mutation in BMPR2 and thus heritable disease. 8 In addition to ge...

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DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway

Cited by 511 publications

References 30 publications

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Nano-formulated curcumin accelerates acute wound healing through Dkk-1-mediated fibroblast mobilization and MCP-1-mediated anti-inflammation

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

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