Identification of XD23 as a potent inhibitor of osteosarcoma via downregulation of DKK1 and activation of the WNT/β-Catenin pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1090468 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28410440_1.fastq.gz | Fastqsanger.gz | |||
| SRR28410440_2.fastq.gz | Fastqsanger.gz | |||
| SRR28410441_1.fastq.gz | Fastqsanger.gz | |||
| SRR28410441_2.fastq.gz | Fastqsanger.gz | |||
| SRR28410442_1.fastq.gz | Fastqsanger.gz |
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Project description:Osteosarcoma, the most prevalent malignant bone tumor, is notorious for its aggressive growth and invasiveness. The highly mutable genome of osteosarcoma has made identifying a key oncogene challenging, hindering the development of targeted treatments. Our study validates the effectiveness of XD23, an anti-cancer agent we previously identified, in curbing osteosarcoma proliferation, metastasis, EMT differentiation, and bone destruction and promoting osteosarcoma apoptosis.
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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.
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Project description:Osteosarcoma, the most prevalent malignant bone tumor, is notorious for its aggressive growth and invasiveness. The highly mutable genome of osteosarcoma has made identifying a key oncogene challenging, hindering the development of targeted treatments. Our study validates the effectiveness of XD23, an anti-cancer agent we previously identified, in curbing osteosarcoma proliferation, metastasis, EMT differentiation, and bone destruction and promoting osteosarcoma apoptosis. It further elucidated that XD23 thwarts osteosarcoma by suppressing DKK1 expression, which in turn activates the WNT-β/Catenin pathway. This research presents the concrete evidence of DKK1's involvement in osteosarcoma development, offering a foundation for the development of DKK1 inhibitors as novel treatments for this disease.
| S-EPMC11402217 | biostudies-literature
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
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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 investigated the effects of DKK1 on melanocyte gene expression profiles and on Wnt signaling pathways using DNA microarray technology. Keywords: compound treatment design
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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.
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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: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 investigated the effects of DKK1 on melanocyte gene expression profiles and on Wnt signaling pathways using DNA microarray technology. Paired cDNA samples, labeled by cyanine 3- and cyanine 5-dUTP incorporation (Qiagen, Valencia, CA) during reverse transcription (Qiagen), were hybridized simultaneously with one oligo-DNA chip (HS-Operon V2vB2.2p13) as per NCI in-house protocol (available at http://mach1.nci.nih.gov/). Two fluorescent intensities of the oligo-DNA chip were scanned using a microarray scanner (GenePix 4000A, Axon Instruments, Inc., Molecular Device Corp., Sunnyvale, CA).
2010-06-30 | E-GEOD-5515 | biostudies-arrayexpress
Project description:We define a pathogenic role for a ß-catenin-activated genetic pathway in murine renal dysplasia. Cre-mediated stabilization of ß-catenin in the ureteric cell lineage prior to the onset of kidney development increased ß-catenin levels and caused renal aplasia or severe hypodysplasia. A genome-wide analysis of mRNA expression in dysplastic tissue identified down-regulation of genes required for ureteric branching and up regulation of Tgfß2 and Dkk1.
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