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Involvement of transcription factor early growth response 4 (EGR4) in lung cancer bone metastasis

ABSTRACT: EGR4 (early growth response 4), a transcription factor, was previously shown to be up-regulated in lung cancer bone metastasis, compared with its expression in metastasis in other organs, using a multiorgan metastasis model of human small-cell lung cancer cells (SBC-5) in NK cell-depleted SCID mice (Kakiuchi S et al. Mol Cancer Res 2003). Here we show that EGR4 was essential for survival cancer cells, and migration ability. Next, in searching of downstream genes regulated by EGR4, we analyzed the changes in transcriptomes of SBC-5 cells at different time-points (24, 48 and 72 hr) when knockdown of EGR4 by siRNA. Lots of genes were identified either up-regulated or down-regulated in siEGR4 samples compared with control siRNA. Among these genes, there were genes with roles in metastasis or bone biology. The fact that EGR4 knockdown led to up-regulation or suppression of these genes also indicated dual roles of EGR4 in transcriptional regulation, which is consistent with previous reports: EGR4 may repress its own promoter (Zipfel PF et al. Biochim Biophys Acta. 1997) or activate certain inflammatory genes (Decker EL et al. Nucleic Acids Res. 2003; Wieland GD et al. J Cell Sci. 2005). SBC-5 cells were cultured at 1x10^6 cells/2 ml in 3.5 cm plate. After seeding 24 hours, cells were transfected either siEGR4 or siEGFP (for control), using Lipofectamin. At 24, 48 and 72 hours after starting of siRNA, we extracted RNA from these cells, and subjected these RNAs to microarray analysis. The labeling, amplification, hybridization and microarray data analysis were described previously (Dat LT et al. Int J Oncol, 40: 1455-1469 2012).

ORGANISM(S): Homo sapiens

SUBMITTER: Dat Le

PROVIDER: S-ECPF-GEOD-40558 | biostudies-other |

REPOSITORIES: biostudies-other

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Involvement of transcription factor early growth response 4 (EGR4) in lung cancer bone metastasis

Project description:EGR4 (early growth response 4), a transcription factor, was previously shown to be up-regulated in lung cancer bone metastasis, compared with its expression in metastasis in other organs, using a multiorgan metastasis model of human small-cell lung cancer cells (SBC-5) in NK cell-depleted SCID mice (Kakiuchi S et al. Mol Cancer Res 2003). Here we show that EGR4 was essential for survival cancer cells, and migration ability. Next, in searching of downstream genes regulated by EGR4, we analyzed the changes in transcriptomes of SBC-5 cells at different time-points (24, 48 and 72 hr) when knockdown of EGR4 by siRNA. Lots of genes were identified either up-regulated or down-regulated in siEGR4 samples compared with control siRNA. Among these genes, there were genes with roles in metastasis or bone biology. The fact that EGR4 knockdown led to up-regulation or suppression of these genes also indicated dual roles of EGR4 in transcriptional regulation, which is consistent with previous reports: EGR4 may repress its own promoter (Zipfel PF et al. Biochim Biophys Acta. 1997) or activate certain inflammatory genes (Decker EL et al. Nucleic Acids Res. 2003; Wieland GD et al. J Cell Sci. 2005).

2013-04-01 | GSE40558 | GEO

Involvement of transcription factor early growth response 4 (EGR4) in lung cancer bone metastasis

2013-04-01 | E-GEOD-40558 | biostudies-arrayexpress

Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone.

Project description:Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment.

| S-EPMC7602858 | biostudies-literature

Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair.

Project description:Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1(-/-) mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1(-/-) mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1(-/-) callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair.

| S-EPMC3169183 | biostudies-literature

Lung cancer bone metastasis

Project description:Lung cancer bone metastasis

| PRJNA934341 | ENA

MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2.

Project description:MicroRNAs (miRNAs) have emerged as key players in cancer progression and metastatic initiation yet their importance in regulating prostate cancer (PCa) metastasis to bone has begun to be appreciated. We employed multimodal strategy based on in-house PCa clinical samples, publicly available TCGA cohorts, a panel of cell lines, in silico analyses, and a series of in vitro and in vivo assays to investigate the role of miR-466 in PCa. Expression analyses revealed that miR-466 is under-expressed in PCa compared to normal tissues. Reconstitution of miR-466 in metastatic PCa cell lines impaired their oncogenic functions such as cell proliferation, migration/invasion and induced cell cycle arrest, and apoptosis compared to control miRNA. Conversely, attenuation of miR-466 in normal prostate cells induced tumorigenic characteristics. miR-466 suppressed PCa growth and metastasis through direct targeting of bone-related transcription factor RUNX2. Overexpression of miR-466 caused a marked downregulation of integrated network of RUNX2 target genes such as osteopontin, osteocalcin, ANGPTs, MMP11 including Fyn, pAkt, FAK and vimentin that are known to be involved in migration, invasion, angiogenesis, EMT and metastasis. Xenograft models indicate that miR-466 inhibits primary orthotopic tumor growth and spontaneous metastasis to bone. Receiver operating curve and Kaplan-Meier analyses show that miR-466 expression can discriminate between malignant and normal prostate tissues; and can predict biochemical relapse. In conclusion, our data strongly suggests miR-466-mediated attenuation of RUNX2 as a novel therapeutic approach to regulate PCa growth, particularly metastasis to bone. This study is the first report documenting the anti-bone metastatic role and clinical significance of miR-466 in prostate cancer.

| S-EPMC5386393 | biostudies-literature

Early growth response-1 induces and enhances vascular endothelial growth factor-A expression in lung cancer cells.

Project description:Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1alpha (HIF-1alpha)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1alpha and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1alpha expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression.

| S-EPMC2893652 | biostudies-literature

Transcription factor ATF3 links host adaptive response to breast cancer metastasis.

Project description:Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell-selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes.

| S-EPMC3696548 | biostudies-literature

Lung cancer bone metastasis

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-16 | GSE225212 | GEO

The transcription factor early growth response factor-1 (EGR-1) promotes apoptosis of neuroblastoma cells.

Project description:Early growth response factor-1 (EGR-1) is an immediate early gene, which is rapidly activated in quiescent cells by mitogens or in postmitotic neurons after depolarization. EGR-1 has been involved in diverse biological functions such as cell growth, differentiation and apoptosis. Here we report that enforced expression of the EGR-1 gene induces apoptosis, as determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end labelling (TUNEL) analysis, in murine Neuro2A cells. In accordance with this role of EGR-1 in cell death, antisense oligonucleotides increase cell viability in cells cultured in the absence of serum. This apoptotic activity of the EGR-1 appears to be mediated by p73, a member of the p53 family of proteins, since an increase in the amount of p73 is observed in clones stably expressing the EGR-1 protein. We also observed an increase in the transcriptional activity of the mdm2 promoter in cells overexpressing EGR-1, which is paralleled by a marked decrease in the levels of p53 protein, therefore excluding a role of this protein in mediating EGR-1-induced apoptosis. Our results suggest that EGR-1 is an important factor involved in neuronal apoptosis.

| S-EPMC1223559 | biostudies-other

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