Preliminary mechanism on the methylation modification of Dkk-1 and Dkk-3 in hepatocellular carcinoma

Liu, Liang; He, He; Lv, Ruixue; Zhang, Mei; Huang, Henjian; An, Zhenmei; Li, Shuangqing

doi:10.1007/s13277-014-2750-y

Cited by 33 publications

(35 citation statements)

References 12 publications

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“…Furthermore, in T2DM, which is closely related to NAFLD [27], circulating DKK-1 was higher in patients than in controls, and associated with endothelial dysfunction, platelet activation and CVD risk [28,29], while they were reduced after improvement in glycemic control [28]. Notably, apart from bone metabolism, the Wnt pathway has been proposed to play a role in the hepato-carcinogenesis [30,31]. More specifically, the abnormal expression and/or methylation of DKK-1 and DKK-3 were reported to play a key role in the abnormal activation of canonical Wnt signaling, resulting in hepatocarcinogenesis [30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, apart from bone metabolism, the Wnt pathway has been proposed to play a role in the hepato-carcinogenesis [30,31]. More specifically, the abnormal expression and/or methylation of DKK-1 and DKK-3 were reported to play a key role in the abnormal activation of canonical Wnt signaling, resulting in hepatocarcinogenesis [30,31]. Given that NASH with IR can lead to hepatocellular carcinoma, even in the absence of liver cirrhosis [32], the trend toward higher DKK-1 levels in NASH than in SS patients might be important, if validated; DKK-1 might be a diagnostic and prognostic serologic marker for early hepatocellular carcinoma, as other authors proposed [33].…”

Section: Discussionmentioning

confidence: 99%

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Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease

et al. 2015

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There is increasing evidence for bone-liver interplay. The main aim of this study was to determine serum sclerostin and Dickkopf (DKK)-1 levels in patients with nonalcoholic fatty liver disease (NAFLD) and their association with the disease severity. Patients with biopsy-proven NAFLD, 13 with nonalcoholic simple steatosis (SS) and 14 with steatohepatitis (NASH), and 20 gender-, age-, body mass index- and waist circumference-matched controls were enrolled. Serum sclerostin, DKK-1, bone turnover markers, vitamin D, insulin and standard biochemical and hematologic parameters were measured; lumbar spinal dual-energy X-ray absorptiometry was performed. We observed that there was a progressive decline in serum sclerostin levels from the controls (76.1 ± 6.8) to SS (53.5 ± 6.4) and NASH (46.0 ± 8.1 pmol/l) patients (p = 0.009); in adjusted pairwise comparisons, sclerostin was significantly higher in the controls than in NASH patients (p = 0.012). Although serum DKK-1 did not differ between groups (p = 0.135), there was a trend toward U-shaped distribution (controls 35.8 ± 2.8; SS 27.3 ± 2.9; NASH 36.8 ± 4.4 pmol/l). Higher DKK-1 levels were independently associated with NASH. Regarding specific histological lesions, DKK-1 levels were marginally lower in NAFLD patients with lower (≤33 %) than higher (>33 %) steatosis grade (27.7 ± 3.1 and 38.8 ± 4.7 pmol/l, respectively; p = 0.049). No other significant difference was observed within histological lesions. In conclusion, serum sclerostin levels were lower in NASH patients than in controls. DKK-1 levels were independently associated with NASH in NAFLD patients. The potential importance of these findings indicates a possible bone-liver interaction and warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease

et al. 2015

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“…The DKK family is comprised of four proteins (DKK1, DKK2, DKK3, and DKK4), which are synthesized as precursor proteins activated by proteolytic cleavage [25]. The DKK1 and DKK3 proteins are the most studied members of the family; these can inhibit Wnt signaling by binding to and degrading coreceptor LRP5/6 and thus have been considered as potential targets in diseases with an aberrant Wnt signaling activity [26, 27]. …”

Section: Wnt Signaling Pathwaysmentioning

confidence: 99%

Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Shi

Luo

et al. 2017

Mediators of Inflammation

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Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases.

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“…Dickkopf-related protein-3 (DKK3) is one of the proteins expressed during the very early stages of hepatogenesis. DKK3 suppresses Wnt-dependent carcinogenic activity by reducing nuclear and cytoplasmic β-catenin accumulation [18]. However, hypermethylation of the DKK3 promoter region suppresses its expression in many cancer cells, including hepatocarinoma [19, 20].…”

Section: Introductionmentioning

confidence: 99%

GATA4 promotes hepatoblastoma cell proliferation by altering expression of miR125b and DKK3

et al. 2016

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GATA4 is a zinc finger DNA-binding protein that plays an important role in mammalian liver development. However, the effects of GATA4 in hepatoblastoma (HB), a common liver cancer in pediatric patients, remain largely unknown. In this study, we demonstrate that GATA4 promotes growth and survival in the Huh6 human hepatoblastoma cell line. GATA4 expression was high in Huh6 cells, and its knockdown decreased expression of Dickkopf-related protein 3 (DKK3), a gene that may contribute to premature or undifferentiated phenotypes in HB. GATA4 also directly bound to the promoter regions of the miRNA miR125b and inhibited its expression in Huh6 cells. DKK3 was a direct target of miR125b in Huh6 cells. Inhibition of miR125b or overexpression of DKK3 promoted proliferation, survival, migration, and invasion in Huh6 cells. This is the first report to demonstrate that GATA4 promotes oncogenesis by inhibiting miR125b-dependent suppression of DKK3 expression. This GATA4/miR125b/DKK3 axis may be a major regulator of growth, migration, invasion, and survival in hepatoma cells, and is therefore a potential therapeutic target or biomarker for progression in HB patients.

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Preliminary mechanism on the methylation modification of Dkk-1 and Dkk-3 in hepatocellular carcinoma

Cited by 33 publications

References 12 publications

Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease

Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease

Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

GATA4 promotes hepatoblastoma cell proliferation by altering expression of miR125b and DKK3

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