Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dysregulation of c-terminal ezrin phosphorylation prevents tumor progression and metastasis and alters cellular metabolism in osteosarcoma

ABSTRACT: This dataset contains Affymetrix Mouse Genome 430 2.0 Array data obtained from K7M2 cells over-expressing ezrinT567A and the wild-type Gene expression analysis of K7M2 cells over-expressing ezrinT567A compared to the wild-type

ORGANISM(S): Mus musculus

SUBMITTER: Chand Khanna

PROVIDER: E-GEOD-33897 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Publications

Dysregulation of ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma.

Ren Ling L Hong Sung-Hyeok SH Chen Qing-Rong QR Briggs Joseph J Cassavaugh Jessica J Srinivasan Satish S Lizardo Michael M MM Mendoza Arnulfo A Xia Ashley Y AY Avadhani Narayan N Khan Javed J Khanna Chand C

Cancer research 20111206 4

Ezrin links the plasma membrane to the actin cytoskeleton where it plays a pivotal role in the metastatic progression of several human cancers; however, the precise mechanistic basis for its role remains unknown. Here, we define transitions between active (phosphorylated open) and inactive (dephosphorylated closed) forms of Ezrin that occur during metastatic progression in osteosarcoma. In our evaluation of these conformations we expressed C-terminal mutant forms of Ezrin that are open (phosphom ...[more]

PMID: 22147261

Similar Datasets

Dysregulation of c-terminal ezrin phosphorylation prevents tumor progression and metastasis and alters cellular metabolism in osteosarcoma

Project description:This dataset contains Affymetrix Mouse Genome 430 2.0 Array data obtained from K7M2 cells over-expressing ezrinT567A and the wild-type

2012-03-14 | GSE33897 | GEO

Dysregulation of ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma.

Project description:Ezrin links the plasma membrane to the actin cytoskeleton where it plays a pivotal role in the metastatic progression of several human cancers; however, the precise mechanistic basis for its role remains unknown. Here, we define transitions between active (phosphorylated open) and inactive (dephosphorylated closed) forms of Ezrin that occur during metastatic progression in osteosarcoma. In our evaluation of these conformations we expressed C-terminal mutant forms of Ezrin that are open (phosphomimetic T567D) or closed (phosphodeficient T567A) and compared their biologic characteristics to full-length wild-type Ezrin in osteosarcoma cells. Unexpectedly, cells expressing open, active Ezrin could form neither primary orthotopic tumors nor lung metastases. In contrast, cells expressing closed, inactive Ezrin were also deficient in metastasis but were unaffected in their capacity for primary tumor growth. By imaging single metastatic cells in the lung, we found that cells expressing either open or closed Ezrin displayed increased levels of apoptosis early after their arrival in the lung. Gene expression analysis suggested dysregulation of genes that are functionally linked to carbohydrate and amino acid metabolism. In particular, cells expressing closed, inactive Ezrin exhibited reduced lactate production and basal or ATP-dependent oxygen consumption. Collectively, our results suggest that dynamic regulation of Ezrin phosphorylation at amino acid T567 that controls structural transitions of this protein plays a pivotal role in tumor progression and metastasis, possibly in part by altering cellular metabolism.

| S-EPMC3867810 | biostudies-literature

Poly (ADP-ribose) polymerase 1 (PARP1) inhibition promotes pulmonary metastasis of osteosarcoma by boosting ezrin phosphorylation.

Project description:Due to the large proportion of BRCA deficiency and chromosomal instability in OS patients, poly (ADP-ribose) polymerase inhibitors (PARPi) could be an effective strategy for anti-OS therapy. In two orthotopic OS mouse models, we discovered that although PARPi had inhibitory effect on the growth of the orthotopic OS tumors regardless of BRCA deficiency, the treatment of PARPi essentially aggravated the pulmonary metastasis of OS in both models. A protein playing a crucial role in OS metastasis, ezrin, was identified as an interactive protein for PARP1. The phosphorylation of ezrin was significantly promoted during PARP inhibition. Besides the traditional function of phosphorylated ezrin at plasma membrane, we newly identified its nuclear speckle localization and its function with mRNA export. Ezrin knockdown or phosphorylation inhibition could partially rescue PARPi induced metastasis. Collectively, we unveiled a new mechanism for PARP-involved OS metastasis, which proposed a novel combinational therapy strategy using PARP and ezrin inhibitors for future OS treatment.

| S-EPMC8771856 | biostudies-literature

SIRT1 promotes metastasis of human osteosarcoma cells.

Project description:Pulmonary metastasis is the leading cause of mortality in patients with osteosarcoma; however, the underlying mechanism remains unclear. The NAD+-dependent deacetylase, sirtuin 1 (SIRT1), has been reported to play a key role in carcinogenesis through deacetylation of important regulatory proteins. Here, we report that SIRT1 promotes osteosarcoma metastasis by regulating the expression of metastatic-associated genes. The SIRT1 protein was significantly upregulated in most primary osteosarcoma tumours, compared with normal tissues, and the SIRT1 expression level may be coupled with metastatic risk in patients with osteosarcoma. Moreover, the results of cell migration and wound-healing assays further suggested that higher expression of SIRT1 promoted invasive activity of osteosarcoma cells. Importantly, downregulating SIRT1 with shRNA inhibited the migration ability of osteosarcoma cells in vitro and suppressed tumour lung metastasis in mice. Finally, a gene expression analysis showed that knockdown of SIRT1 profoundly activated translation of its downstream pathway, particularly at migration and invasion. In summary, high levels of SIRT1 may be a biomarker for a high metastatic rate in osteosarcoma patients; inhibiting SIRT1 could be a potent therapeutic intervention for these patients.

| S-EPMC5346743 | biostudies-literature

Cofilin dysregulation alters actin turnover in frataxin-deficient neurons.

Project description:Abnormalities in actin cytoskeleton have been linked to Friedreich's ataxia (FRDA), an inherited peripheral neuropathy characterised by an early loss of neurons in dorsal root ganglia (DRG) among other clinical symptoms. Despite all efforts to date, we still do not fully understand the molecular events that contribute to the lack of sensory neurons in FRDA. We studied the adult neuronal growth cone (GC) at the cellular and molecular level to decipher the connection between frataxin and actin cytoskeleton in DRG neurons of the well-characterised YG8R Friedreich's ataxia mouse model. Immunofluorescence studies in primary cultures of DRG from YG8R mice showed neurons with fewer and smaller GCs than controls, associated with an inhibition of neurite growth. In frataxin-deficient neurons, we also observed an increase in the filamentous (F)-actin/monomeric (G)-actin ratio (F/G-actin ratio) in axons and GCs linked to dysregulation of two crucial modulators of filamentous actin turnover, cofilin-1 and the actin-related protein (ARP) 2/3 complex. We show how the activation of cofilin is due to the increase in chronophin (CIN), a cofilin-activating phosphatase. Thus cofilin emerges, for the first time, as a link between frataxin deficiency and actin cytoskeleton alterations.

| S-EPMC7090085 | biostudies-literature

Auranofin is a potent suppressor of osteosarcoma metastasis.

Project description:Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5-year survival rate of only 10-20%. Therefore, identifying the genes and pathways involved in metastasis, as new therapeutic targets, is crucial to improve long-term survival of OS patients. Novel markers that define metastatic OS were identified using comparative transcriptomic analyses of two highly metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5) isolated from the metastatic OS cell line, KHOS. Using this approach, we determined that the metastatic phenotype correlated with overexpression of thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF). Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly expressed in 29-42% of metastatic OS patient biopsies, with no detectable expression in non-malignant bone or samples from OS patients with localised disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a significant effect on cell viability whereas at higher doses, AF could induce ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the development of pulmonary metastasis and we provide evidence that this effect may be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a novel druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with OS.

| S-EPMC4808036 | biostudies-literature

FOXC2 augments tumor propagation and metastasis in osteosarcoma.

Project description:Osteosarcoma is a highly malignant tumor that contains a small subpopulation of tumor-propagating cells (also known as tumor-initiating cells) characterized by drug resistance and high metastatic potential. The molecular mechanism by which tumor-propagating cells promote tumor growth is poorly understood. Here, we report that the transcription factor forkhead box C2 (FOXC2) is frequently expressed in human osteosarcomas and is important in maintaining osteosarcoma cells in a stem-like state. In osteosarcoma cell lines, we show that anoikis conditions stimulate FOXC2 expression. Downregulation of FOXC2 decreases anchorage-independent growth and invasion in vitro and lung metastasis in vivo, while overexpression of FOXC2 increases tumor propagation in vivo. In osteosarcoma cell lines, we demonstrate that high levels of FOXC2 are associated with and required for the expression of osteosarcoma tumor-propagating cell markers. In FOXC2 knockdown cell lines, we show that CXCR4, a downstream target of FOXC2, can restore osteosarcoma cell invasiveness and metastasis to the lung.

| S-EPMC5356590 | biostudies-literature

Patrolling monocytes inhibit osteosarcoma metastasis to the lung.

Project description:Immune infiltration is associated with osteosarcoma metastasis. However, previous studies have not accounted for the functional diversity of the cells involved in the immune response. We conducted a comprehensive comparative analysis of the tumor-infiltrating immune cells in metastatic and non-metastatic osteosarcoma tissues based on a deconvolution algorithm (CIBERSORT). Twenty-two immune cell subsets were evaluated for their association with the presence or absence of metastasis in osteosarcoma patients. A lack of monocytes was associated with osteosarcoma metastasis; however, the levels of M1 macrophages, M2 macrophages and other immune cell subsets did not differ between the metastatic and non-metastatic groups. Additionally, a higher proportion of monocytes was associated with a better prognosis in osteosarcoma patients. Animal experiments demonstrated that the number of metastatic nodules was higher in mice lacking patrolling monocytes than in control mice. Our data indicated that the cellular composition of the immune infiltrate may subtly differ among osteosarcoma patients, and that patrolling monocytes inhibit osteosarcoma metastasis to the lungs of mice. Thus, the composition of the immune infiltrate and the level of patrolling monocytes may be important determinants of whether metastasis occurs in osteosarcoma patients.

| S-EPMC7746373 | biostudies-literature

Intrinsic epigenetic state of primary osteosarcoma drives metastasis.

Project description:Osteosarcoma (OS) is the most common primary malignant bone tumor affecting the pediatric population with high potential to metastasize to distal sites, most commonly the lung. Insights into defining molecular features contributing to metastatic potential are lacking. We have mapped the active chromatin landscapes of OS tumors by integrating histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary OS tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared to primary tumors from patients without metastatic disease (localized). The difference in chromatin activity shapes the transcriptional profile of OS. We identified novel candidate genes involved in OS pathogenesis and metastasis, including PPP1R1B, PREX1 and IGF2BP1, which exhibit increased chromatin activity in primary met along with higher transcript levels. Overall, differential chromatin activity in primary met occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and extracellular matrix suggestive of their role in facilitating OS metastasis. Furthermore, chromatin profiling of tumors from metastatic lung lesions noted increases in chromatin activity in genes involved in cell migration and key intracellular signaling cascades, including the Wnt pathway. Thus, this data demonstrates that metastatic potential is intrinsically present in primary metastatic tumors and the cellular chromatin profiles further adapt to allow for successful dissemination, migration, and colonization at the distal metastatic site.

| S-EPMC10680799 | biostudies-literature

Phosphorylation prevents polyglucosan transport in Lafora disease.

Project description: Not available

| S-EPMC3385497 | biostudies-literature