Effect of DKK1 on embryo elongation
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ABSTRACT:
ORGANISM(S): Bos taurus
PROVIDER: GSE126680 | GEO | 2019/03/29
REPOSITORIES: GEO
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Project description:Effect of DKK1 on embryo elongation
| PRJNA522975 | ENA
Project description:Canonical Wnt signaling controls proliferation and differentiation of osteogenic progenitor cells, and tumor-derived secretion of the Wnt antagonist Dickkopf-1 (Dkk1) is correlated with osteolyses and metastasis in many bone malignancies. However, the role of Dkk1 in the oncogenesis of primary osteosarcoma (OS) remains unexplored. Here, we over-expressed Dkk1 in the OS cell line MOS-J. Contrary to expectations, Dkk1 had autocrine effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro. In vivo, Dkk1 expressing MOS-J cells formed larger and more destructive tumors than controls. These effects were attributed in part to up-regulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1) through Jun-N-terminal kinase signaling. This is the first report linking Dkk1 to tumor stress resistance, further supporting the targeting of Dkk1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells. Two samples were analyzed, one human DKK1 transfected MOS-J cell sample and one control vector transfected MOS-J cell sample.
2012-12-22 | E-GEOD-43112 | biostudies-arrayexpress
Project description:Successful embryonic development depends upon molecules secreted by the reproduc-tive tract. Among such molecules is dickkopf 1 (DKK1), an canonical WNT antagonist that can also activate the planar cell polarity (PCP) pathway. Objectives were to determine whether DKK1 regulates expression of genes that promote differentiation, possibly through the PCP pathway, and to determine if actions of DKK1 on the embryonic transcriptome were dependent on embryo sex. Bovine oocytes were fertilized with pools of X- or Y-sorted sperm. Embryos were treated with 100 ng/ml DKK1 or vehicle at Day 5 of development and harvested 24 h later for microarray analysis of global gene expression. A total of 9,931 transcripts were identified as being expressed. with124 being differentially expressed genes between females and males. A total of 68% of the genes upregulated in females were located on the X chromosome. DKK1 changed expression of 132 genes in females and 136 in males. Of these, 34 genes were regulated by DKK1 in both sexes - 14 in the same direction and 20 in opposite directions. Evidence for regulation of the PCP pathway by DKK1 was the finding that DKK1 regulated expression of genes involved in cell polarization and differentiation in both females and males. In both sexes, DKK1 regulated expression of many genes associated with HNF4A, a marker of hypoblast cells that promotes formation of cell junctions. In conclusion, DKK1 regulates cell differentiation and embryonic development in a sex-dependent manner and effects may be mediated, at least in part, by activation of the PCP pathway. Bovine embryos produced with X- or Y-sorted sperm were cultured in vitro and treated with vehicle or DKK1 at day 5 of development and harvested at day 6 for RNA isolation, amplification and hibridization to Affymetrix Bovine Gene 1.0 ST arrays. The study was done in 5 replicates using pools of 20 morulae for each treatment.
2014-08-06 | E-GEOD-60098 | biostudies-arrayexpress
Project description:Canonical Wnt signaling controls proliferation and differentiation of osteogenic progenitor cells, and tumor-derived secretion of the Wnt antagonist Dickkopf-1 (Dkk1) is correlated with osteolyses and metastasis in many bone malignancies. However, the role of Dkk1 in the oncogenesis of primary osteosarcoma (OS) remains unexplored. Here, we over-expressed Dkk1 in the OS cell line MOS-J. Contrary to expectations, Dkk1 had autocrine effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro. In vivo, Dkk1 expressing MOS-J cells formed larger and more destructive tumors than controls. These effects were attributed in part to up-regulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1) through Jun-N-terminal kinase signaling. This is the first report linking Dkk1 to tumor stress resistance, further supporting the targeting of Dkk1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells.
2012-12-22 | GSE43112 | GEO
Project description:Super Enhancers are a class of DNA Cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis.Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, current research is far from sufficient to reveal the complex mechanisms behind epigenetic modifications.The aim of this study is to explore the function and mechanism of a new Super Enhancer in Pancreatic ductal adenocarcinoma (PDAC) tumors. By using epigenetic modification and chromatin interaction information, we found a new Super Enhancer enriched with abnormal active histone modifications in PDAC tumors and cells, called DKK1-super-enhancer (DKK1-SE).DKK1-SE was grouped according to the activity modification information, and the e1 component was identified as the main active unit by dual luciferase reporter gene system and dCas9-KRAB system.DNA motif analysis and core site deletion assay revealed that the e1 component possessed AP1 transcription factor family binding sites.Mechanically, AP1 activates DKK1 transcriptional activity by recruiting JUND and FOSL2 to induce enhancer chromatin remodeling.CRISPR/ Cas9-mediated deletion of DKK1-SE resulted in significant downregulation of its target gene DKK1.Analysis of TCGA data of PDAC tumors combined with immunohistochemical results of PDAC patients demonstrated that DKK1 was closely related to malignant clinical features of PDAC.Bioinformatics analysis of RNA-seq data showed that DKK1 was mainly related to tumor-related biological functions such as extracellular matrix, cell adhesion, angiogenesis, and cell proliferation.Cell malignant phenotype assay showed that deletion or interference of DKK1-SE significantly inhibited the proliferation, colony formation, migration and invasion of PANC-1, and these phenomena were partially alleviated after restoring DKK1 expression in DKK1-SE deficient cells.Experiments of Subcutaneous transplantation tumor in nude mice and Orthotopic transplantation tumor model showed that DKK1-SE deletion not only inhibited tumor proliferation, but also reduced the complexity of tumor microenvironment, resulting in less angiogenesis of tumor tissues and reduced fibrosis degree.In conclusion, DKK1-SE drives the expression of DKK1 by recruiting AP1 family transcription factors, which plays a carcinogenic role in PDAC tumors and enhances the complexity of the tumor microenvironment.
2023-12-12 | GSE248887 | GEO
Project description:Dickkopf 1 (DKK1), which is expressed at high mRNA levels by fibroblasts in the dermis of human skin on the palms and soles, inhibits the function and proliferation of melanocytes in the epidermis of those areas via the suppression of beta-catenin and microphthalmia-associated transcriptor factor (MITF). In this study, we report that treatment of keratinocytes with DKK1 increases their proliferation and decreases their uptake of melanin, and that treatment of reconstructed skin with DKK1 induces a thicker and less pigmented epidermis. We investigated the effects of DKK1 on keratinocytes using DNA microarray technology. Keywords: compound treatment design
2007-12-31 | GSE9211 | GEO
Project description:Cancer cachexia with profound weight loss and frailty impairs quality of life, limits cancer therapy and decreases survival, against which no effective therapy is available. Dkk1 is a secreted antagonist of Wnt/β-catenin pathway via interacting with Wnt co-receptors LRP5 and 6 (LRP5/6) and inducing their endocytosis1-4. Although Dkk1 is critical for animal development3,5, its mRNA is undetectable in most adult organs6. Of note, elevated circulating Dkk1 leads to poor prognosis in patients with a variety of types of cancer by a completely unknown mechanism. Here, we show that administration of a recombinant Dkk1 protein accelerated cancer cachexia-related death through inducing LRP6 endocytosis but not β-catenin inhibition, whereas pharmacological blockade of Dkk1-induced membrane LRP6 downregulation completely prevented cancer cachexia and robustly prolonged survival in tumor-bearing mice. Pharmacological blockade of Dkk1-induced membrane LRP6 downregulation prevented alterations of a number of GPCR pathways and all main cancer cachexia-related pathways in skeletal muscle of mice bearing tumor as shown by a genome-wide transcriptional analysis. Furthermore, Dkk1 injection into hindlimb directly triggered activations of GPCR pathways and cachexia-related pathways. These findings establish a key role of the Dkk1-LRP6 axis in cancer cachexia development through affecting GPCR pathways and suggest a highly promising therapeutic approach for preventing cancer cachexia.
2024-12-01 | GSE121873 | GEO
Project description:DKK1 recruits osteoclast precursor cells in a concentration gradient-dependent manner. In order To clarify the transcriptome changes when osteoclast precursor cells are recruited by DKK1.We compared the expression profiles of osteoclast precursor cells with or without DKK1 stimulation.
2023-09-16 | GSE184248 | GEO
Project description:Infection with oncogenic human papillomavirus (HPV) is a major cause for the development of cervical cancer, which is mainly driven by the expression of the HPV E6 and E7 oncoproteins. We uncovered that the concentration levels of the putative tumor suppressor Dickkopf-1 (Dkk1) are restricted in cervical cancer cells by HPV E6 expression due to the E6-mediated proteolytic degradation of p53, which is a transcriptional regulator of Dkk1. Moreover, we found that Dkk1 is critically involved in the pro-apoptotic Cisplatin response of these cells, as Dkk1 repression was associated with an increased resistance towards the chemotherapeutic compound. This could be of high relevance for cervical cancer treatments, which usually involve Cisplatin for standard care. Although Dkk1 is a major antagonist of the canonical Wnt signaling, the differential response towards Cisplatin observed in Dkk1-depleted cells was not associated to an activation of this pathway. To elucidate alternative underlying mechanisms, we performed Affymetrix Gene Expression analyses comparing the transcriptome of Cisplatin-treated parental HeLa to CRISPR/Cas9-generated Dkk1 knockout (KO) HeLa cells. These revealed that Dkk1 depletion is linked to an impairment of the pro-apoptotic JNK/AP-1 pathway in cervical cancer cells, suggesting that Dkk1 drives Cisplatin-mediated apoptosis via activation of this signaling hub.
2022-08-16 | GSE200748 | GEO
Project description:With the improvement of people's living standards and lifestyle changes, nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. However, few drugs are available for NAFLD, partly due to an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of function approaches, we identified DKK1 as a pivotal mediator of the progression of NAFLD and its accompanying metabolic disorders in dietary obese mice. Mechanistic study reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through ERK-PPARγ-CD36 pathway. Moreover, DKK1 increased insulin resistance by activating the JNK signaling pathway, which in turn exacerbates disorders of hepatic lipid metabolism. These results suggest that DKK1 is a regulator of fatty acid uptake in lipid metabolism and insulin signaling, and may be a potential therapeutic candidate for NAFLD
2022-11-19 | GSE197746 | GEO