Targeted Knockdown of EGR-1 Inhibits IL-8 Production and IL-8-mediated Invasion of Prostate Cancer Cells through Suppressing EGR-1/NF-κB Synergy

Ma, Jiajia; Ren, Zijia; Ma, Yang; Xu, Lu; Zhao, Ying; Zheng, Chaogu; Fang, Yinghui; Xue, Ting; Sun, Baolin; Xiao, Weihua

doi:10.1074/jbc.m109.016246

Cited by 63 publications

(56 citation statements)

References 30 publications

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“…Moreover, the expression of some NF-kB-associated proinflammatory transcription factors such as EGR-1 can be induced by a range of stimuli, including NF-kB activators (36)(37)(38). As expected, both NF-kB and EGR-1 were positively involved in chemokine induction by Nod2 activation in the current study (Fig.…”

Section: Atf3 Induction Suppresses Proinflammatory Transcription Factsupporting

confidence: 59%

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Park

Hun

Choi

et al. 2013

The Journal of Immunology

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In response to excessive nucleotide-binding oligomerization domain–containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-κB and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-κB regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-κB, which contributes to the suppression of Nod2-activated proinflammatory gene expression.

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Section: Atf3 Induction Suppresses Proinflammatory Transcription Factsupporting

confidence: 59%

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Park

Hun

Choi

et al. 2013

The Journal of Immunology

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“…Alternatively, it is also possible that MMP-9 transcriptional activity, which is dependent on NF-B, 53 is linked to the ability of EGR-1 to suppress the NF-B pathway. 54 EGR-1 is indeed known to repress NF-B transcriptional activity in a regulatory way by preventing its interaction with promoter targets element. 55 As discussed in the previous paragraph, it is also possible that EGF/EGR-1 induces the expression of transcriptional suppressors, such as TGF␤1, a gene that is often associated with the repressive activity of EGR-1.…”

Section: Discussionmentioning

confidence: 99%

EGR-1 activation by EGF inhibits MMP-9 expression and lymphoma growth

Bouchard

Bélanger

Biron-Pain

et al. 2010

Blood

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IntroductionRecent evidence has reinforced the notion that the tumor microenvironment plays a key role in the growth and survival of hematologic malignancies. [1][2][3] In this tumor microenvironment, cancer cells are surrounded by numerous cell types including endothelial cells (ECs) of the blood and lymphatic circulation, stromal fibroblasts and a variety of bone marrow-derived cells. 4 Stromal cells express a wide variety of chemokine and growth factor receptors, rendering them responsive to the local production of soluble mediators, most notably during close contact with lymphoma cells. Interactions of tumor cells with these stromal elements are believed to be critical in the initiation and progression of the oncologic process. 5,6 For example, we have previously shown that close contact between lymphoma cells and ECs leads to the expression of several matrix metalloproteinases (MMPs), including MMP-9. 7-9 Proteolytic remodeling of extracellular matrix in tumor progression by hostderived MMP-9 has also been observed both in vivo and in vitro in human and experimental models of cancers. [10][11][12][13][14] While absence of MMP-9 does not prevent development of thymic lymphoma, 15 abnormally high levels of MMP-9 has been shown to accelerate the growth of thymic lymphoma. 14 However, while a large number of studies have focused on the molecular mechanisms that control the induction of MMPs in stromal cells, [16][17][18][19][20] the nature of the signals that suppress MMP-9 secretion in peritumoral cells remains largely unknown.The early growth response protein 1 (EGR-1) is a member of the immediate early gene family of transcription factors containing a DNA-binding domain consisting of 3 zinc fingers that regulates transcription through guanine-cystosine-rich, cis-acting promoter elements. 21,22 EGR-1 controls the expression of a wide variety of genes, many of which play a pivotal role in the regulation of cell growth, differentiation, and apoptosis. 23 However, although several studies have shown that EGR-1 promotes cancer progression [23][24][25] there is increasing evidence that EGR-1 may also exert tumor suppression. [26][27][28][29][30] In leukemia, for instance, EGR-1 has been implicated in the apoptosis of myeloma cells via its interaction with c-JUN while it behaves as a tumor suppressor against the oncogenes E2F-1 and c-MYC. [31][32][33] In the present study, we found that EGR-1 gene expression is induced in stromal cells upon close contact with lymphoma cells, an effect that is mediated by the epidermal growth factor (EGF). Using in vivo and in vitro experimental models, we further found that de novo expression of EGR-1 induced by EGF inhibits the expression of MMP-9 and decreases the growth of thymic lymphoma. Methods MiceBreeder pairs for the C57BL/6 mouse colony were purchased from The Jackson Laboratory. The proMMP9-Luc transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome were generated in the 129 background by standard microinjection techniques. Transgenic founders...

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“…Aberrant expression of genes with functions in drug response, angiogenesis, apoptosis, and cell survival, to name a few, often contributes notably to the acquisition of drug resistance. EGR-1, an important transcription factor that increases cell survival, is overexpressed in a majority of human cancers and contributes to tumorigenesis (18,41,42). Overexpression of MDR-1 in cancer cells increases cellular drug efflux and causes resistance to multiple drugs (43).…”

Section: Discussionmentioning

confidence: 99%

Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells

Lin¹,

Chien²,

Lee³

et al. 2011

J. Clin. Invest.

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Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.

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Targeted Knockdown of EGR-1 Inhibits IL-8 Production and IL-8-mediated Invasion of Prostate Cancer Cells through Suppressing EGR-1/NF-κB Synergy

Cited by 63 publications

References 30 publications

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

EGR-1 activation by EGF inhibits MMP-9 expression and lymphoma growth

Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells

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