Introduction

Early growth response-1 (EGR-1) is a member of early growth response proteins family that has been studied in a variety of physiological progress and identified as the downstream molecules of growth factors, hormones, neurotransmitters and metabolite [1]. EGR-1 as a transcription factor is susceptible to hypoxia, fluid shear stress and vascular injury rapidly [2]. Early growth response proteins family is categorized by an identical protein organization that encompasses four family numbers: EGR-1, EGR-2, EGR-3 and EGR-4 [3, 4]. The identical protein organization is characterized by three zinc fingers component conserved regions in the C-terminus achieving interaction with the target genes that harbor specific GC-rich consensus sequences [1]. Transcriptional activation domain, orienting in the N-terminus, holds the binding sites for other proteins that augment the transcriptional control of EGR-1. Linking the activation domain and the DNA-binding domain is the inhibitory domain that provides binding sites for transcriptional co-factors, NAB1 and NAB2, both are inhibitors of EGR-1 biological activation. Besides, CArG elements, a kind of serum response elements (SREs), located in the EGR-1 promoter are essential for radiation and chemotherapy by target the consensus sequence CC(A/T)6GG. Mechanism research indicated that CArG elements also regulated multiple immediate-early genes after stimulated by mitogenic (Fig. 1).

Fig. 1
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Schematic representation of EGR-1-encoded protein

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Analogous to EGR-1, transcription factor Sp1 inclines to bind the GC-rich sequence as well. It is tempting to speculate that Sp1 and EGR-1 compete for the overlapping sites of target genes [5]. Initially, EGR-1 was known for the “facilitated inhibition” of Sp1 trans-activation activity for inhibiting Sp1 binding to the GC-rich region [6, 7]. A string of studies have testified that Sp1 transcriptionally activate numerous oncogenes in human cancers cells. Comparatively, EGR-1 is a cancer suppressor for blunting the activation of Sp1 via “facilitated inhibition” effect [8, 9]. Preliminary indication of the effect of EGR-1 in cancers has been made, whereas defined EGR-1 as an anti-oncogene still far less certain. In further studies, EGR-1 has been identified as an early response gene to ionizing radiation. Mechanism analysis manifested that ionizing radiation could increase the transcription of EGR-1 via trigger the transcriptional activation domain, and then, upregulated EGR-1 synergistically intensified tumor cell apoptosis in various parallel signaling pathways [10]. Noteworthy was that EGR-1 boosted PTEN-induced apoptosis after ionizing radiation, following a directly binding site detected in the 5′ non-coding regions of PTEN [11]. CArG elements in the promoter of EGR-1 are the structural basis for synergistic kill effect of EGR-1 after ionizing radiation in cancer cells. For that, a suicide gene therapy vector was built in the method to put EGR-1 promoter in the upstream of GADD45α cDNA. Vitro models indicated that vector suppressed lung cell proliferation combined with resveratrol [12]. In a sense, gene vectors provide new strategies for the treatment of malignant tumors.

A number of heterogeneous natural compounds involved in modulating the biological property of EGR-1 in cancer development (Table 1). Notably, curumian inhibited EGR-1 expression, and kept a significant antitumor effect, while resveratrol promoted cancer cells apoptosis by the way of increasing the expression of EGR-1 [4, 13]. Similarly, a mount of cell-signaling studies provided that EGR-1 was the downstream of MAPK/ERK signal pathway that kept a role in promoting the survival of tumor cells. On the other hand, EGR-1 also induced tumor cells apoptosis via regulating the expression of NAG-1 and PTEN [14,15,16]. Several discrepancy could illustrate the controversial results of EGR-1 in cancer, like the tumor types, some known or unknown signaling pathways as well as specific functions of EGR-1. In our review, we have evaluated the effects of EGR-1 in tumor cell proliferation, apoptosis, migration, invasion and tumor microenvironment, and then summarized the possible signaling events that mediated by EGR-1 in cancers.

Table 1 Natural compounds can modulate the biological property of EGR-1 in the context of cancer development
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EGR-1 in DNA repair mechanisms

p53 gene as an anti-oncogene has been widely discovered by researchers and kept a high correlation with human tumors. Protein p53, a tetrameric transcription factor, was initially described as “the guardian of the genome”. The ability of p53 protein is DNA-damage monitoring and conserving stability. In recent years, anticancer activity of p53-lacked cells provided a new view to tumor treatment. EGR-1 has been detected for the function of inducing p53-lacked prostate cells apoptosis via increasing the expression of tumor necrosis factor-α (TNF-α) [10]. Acting in concert, EGR-1 and p53 combination could potentiate the anticancer efficiency of cisplatin in NSCLC xenografts mice [17]. Meanwhile, EGR-1 and p53 are also essential in the quercetin-mediated colon carcinoma cells apoptosis [18]. p21 represents a major target of p53 activity and a focal point of DNA damage as well as cell cycle arrest. Studies have indicated that p21 was the primary mediator of cell cycle regulation after p53 activation. Choi and coworkers reported that EGR-1 augmented the p21 gene expression, and then induced cancer cell apoptosis independent of p53 in DNA repair processes [19].

p53 gene mutation could be detected in a myriad of human cancers [20]. A study showed that p53 protein 156, 246, 247 and 273 point mutations hold high affinity with EGR-1 activation [21]. Further explorations on prostate cancer have indicated that mutant p53 initiated ERK1/2-mediated upregulation of EGR-1, in turn, a feedback loop of EGR-1/EGFR/ERK also detected [22]. Taken together, these findings showed that EGR-1 made a central role in DNA repair mechanisms under the physiological conditions, however, EGR-1 exacerbated the tumor progression after p53 mutation.

EGR-1 augments cell proliferation

Cell proliferation is a dynamic process that relies on various growth factors. High expression of growth factor and its receptor is a characteristic change of cancer cells. The earlier data demonstrated that upregulation of EGR-1 has been recognized as a potent prostate cancer event. Moreover, the protein level of EGR-1 in prostate cancer tissues kept positive correlation with Gleason scores and remarkable increase could be detected in 8–10 scores patients than those at lower Gleason scores [23]. Similar conclusion also appropriated in gastric cancer, for that EGR-1 at a high level when the patients diagnosed at malignant histological grade [24]. MAPK/ERK pathway is a classical proliferation signaling pathway which is triggered by growth factors. Treated with the MAPK/ERK pathway inhibitor, PD98059, EGR-1 expression level significantly reduced in vitro test, which implied that EGR-1 was the downstream gene of the MAPK/ERK pathway [25]. Furthermore, evidence has revealed that attenuated the nuclear fraction of EGR-1 pronounced suppressed breast cancer cells survival by means of inhibiting MAPK phosphorylation [26]. It was worth mentioning, transient overexpression of EGR-1 not only reinforced tumor growth, but also activated the p38 MAPK-signaling pathway [27].

Cyclin D1, a cell cycle regulatory molecule, induces cell proliferation via promoting G1 phase into S phase. Mitogen might increase cyclin D1 expression, utilizing the ERK signaling pathway activation [28]. Besides, bombesin-induced cell proliferation has been identified related to the activation of the MAPK pathway. Activated MAPK pathway enhanced the interaction of EGR-1 and cyclin D1, and then increased the cyclin D1 protein level in prostate cancer cells [29, 30]. Similarly, JNKs, another member of the MAPK family, also increased the expression of EGR-1 [31].

In principle, the mechanism of EGR-1 in cancer cell proliferation is a circular process. As the first step, EGR-1 as well as numerous growth factor activates the MAPK/ERK signaling pathway, then the activated MAPK/ERK signaling pathway further strengthen the expression of EGR-1. Up-regulated EGR-1 promotes cell proliferation via regulation cell cycle protein expression, and continue to enhance the activation of MAPK/ERK-signaling pathway by a positive feedback loop. Need to supplement, other growth factors, like insulin-like growth factor-1 (IGF-1) and its receptor, also hold the mobilizing function of the MAPK/ERK signaling pathway (Fig. 2).

Fig. 2
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The pathway of EGR-1 regulating cancer cell proliferation

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EGR-1 promotes cell apoptosis

Apoptosis is a procession of programmed cell death, which occurs in physiological condition. Following the awareness of the anticancer functions of nonsteroidal anti-inflammatory drugs (NSAIDs), the underlying mechanisms have been extensively explored. Without rival, the NSAID-activated gene-1 (NAG-1) is a crucial regulator in NSAIDs-mediated multiform tumor cell growth arrest, whether rely on COX-2 or not, which belongs to the transforming growth factor-β (TGF-β) superfamily. Studies have detected an EGR-1-binding site in the promoter of NAG-1. Meanwhile, EGR-1 expression obviously facilitated NAG-1-mediated colon carcinoma cells, lung cancer cells and hepatocellular carcinoma cells apoptosis [32, 33]. Importantly, NSAIDs could directly up-regulate EGR-1-mediated NAG-1 expression, and then promoted cell apoptosis in a COX-2-independent manner. By either route, NSAIDs induced apoptosis on a COX-2-dependent manner by driving the activation of the PPARγ/EGR-1/NAG-1 signal pathway [34]. It is worth mentioned, amounts of natural compounds, drugs and molecules keep ability of anticancer via the EGR-1/NAG-1-mediated cell apoptosis (Table 2).

Table 2 Natural compounds, drugs and molecules keep ability of anticancer via the EGR-1/NAG-1-mediated cell apoptosis
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Phosphatase and tensin homolog (PTEN) is an important tumor suppressor gene. Virolle T and partners have found an Egr-1-binding site in the PTEN 5′-untranslated region. This suggests that EGR-1 could regulate PTEN expression and trigger cancer cells apoptotic via target the promoter of it. In breast cancer, studies indicated insulin-like growth factor-II (IGF-II) increased EGR-1-mediated PTEN expression [35]. Analogously, unconjugated bilirubin (UCB) activated APE1/Ref-1 pathway, and then promoted EGR-1 transcriptional regulated PTEN expression [36]. Vitamin D induced apoptosis of cancer cells via increasing PTEN expression in a vitamin D receptor, Egr-1 and p300 synergistic manner [37].

EGR-1 regulates cell metastasis

In malignant carcinomas, distant metastasis is always concurrent with poor prognosis. Originally, epithelial–mesenchymal transition (EMT) was discerned in embryogenesis. Through the multiple strategies and tools displayed by cancer cells to gain metastasis advantages, EMT is one of the most concealed. In the tumor progress, EMT refers to epithelial cells not curbing their movements in the epithelial cell layer and orienting to the mesenchymal cells layer, following significant morphology changes that from epithelial to mesenchymal morphology. Given that premise, EMT has been extensively delved into the regulation of cell invasion, intravasation and systemic dissemination. EMT-TFs, a series of transcription factors, orchestrate the EMT programs [38]. E-cadherin is an EMT-TF with extensive research as the key regulator to maintain cell–cell adhesion and its repression promotes cells break through the basement membrane. Similarly, Snail is indicated to enhance the expressions of mesenchyme genes, such as matrix metalloproteinase-9 (MMP9) and zincfinger ebox binding homeobox 1 (ZEB1), or reduce the protein level of epithelium marker [39]. CXCL5/ENA78, a CXC-type chemokine, is capable of promoting the expression of Snail via increasing Raf/MEK/ERK pathway-mediated EGR-1 transcription in the hormone-independent prostate cancer [40]. In ovarian cancer cell, epidermal growth factor (EGF) not only increases the invasive capability by the way of p38 MAPK-triggered Snail upregulation, but also upregulates Slug via ERK1/2 and PI3 K/Akt-mediated EGR-1 overexpression (Fig. 3) [41].

Fig. 3
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The pathway of EGR-1 affecting cancer cell metastasis

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Besides EMT, cancer stem cells (CSCs) are another modulator of tumors distant metastasis. CSCs also termed as the tumor-initiating cells, have been widely detected in cells aggression and self-renewal, which kept high correlation with the progression of dormancy, colonization and secondary tumor formation in cancer metastasis. In the hypoxia condition, EGR-1 could inhibit the growth of breast cancer stem spheroids [42].

Additionally, Shao G investigated the regulation ability of EGR-1 in prostate cancer and its relationship to metastasis. It showed inactivating EGR-1 may attenuate IL-6-related prostate cancer metastases through weakening PI3 K/PTEN/Akt signaling pathway [43]. As a pleiotropic transcription factor, EGR-1 also promoted ionizing radiation-induced EMT in non-small cell lung cancer cells via the mut-p53/Egr-1/cathepsin L axis [44]. This suggests that the metastatic cascade is an especially complex, multipotent and high-synergistic biological process, rather than assembling one molecule after another.

EGR-1 in tumor microenvironment

Stephen Paget described the interplay between tumor and its microenvironment using the “seed and soil” theory in 1889. That is to say, the tumor cells was the seed that rooted in the tumor microenvironment.

Angiogenesis is an important physiology and pathology process in wound healing and tissue repair. Besides, angiogenesis also accelerated tumors getting the malignant characteristic and angiogenesis inhibitors have been extensively used in the therapeutic of cancers [45]. 5-Fluorouracil (5-FU), a potent anticancer drug, is commonly used in solid tumors chemotherapy. Thrombospondin-1 (TSP-1) has emerged as an angiogenesis suppressor for that inhibiting vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) expression, promoting endothelial cell apoptosis, and attenuating circulating endothelial cell progenitors. Increasing evidence verified that 5-FU augmented the p38 MAPK pathway mediated EGR-1 up-regulation, and then EGR-1 enhanced TSP-1 gene transcription by the way of identifying the transcriptional regulatory element in its promoter in human colon cells [46, 47]. Moreover, EGR-1 could increase the angiogenic growth factors basic fibroblast growth factor (bFGF) and VEGF transcription directly. Nevertheless, sustained expression of EGR-1 led a feedback inhibit of bFGF and VEGF expression that regulated by the corepressor NAB2 [48]. Besides, fibroblast growth factor 2 (FGF-2) is a key downstream target of EGR-1 as well that has been widely studied in anti-angiogenic therapies [49, 50].

Hypoxia is a powerful stimulator of angiogenesis that accompany with significant heterogeneity in endothelial cells. Hypoxia-inducible factors (HIFs) primarily activated when cells sensed the low oxygen tension, and then up-regulated HIFs mediated the transcriptional responses to hypoxia [51]. To improve intratumoral hypoxia, HIFs enhanced the expression of VEGF family members that promoted neovascularization through formation new capillaries from preexisting vessels, maintaining tumor cells survival in a hostile microenvironment [52,53,54]. Further exploration indicated that EGR-1 induced by ERK1/2 pathway augmented HIF-1α-mediated VEGF-A expression in the hypoxic microenvironment. Besides, EGR-1 directly activated VEGF-A expression by binding to the proximal region of the VEGF-A promoter in lung cancer cells [55]. Lymphatic endothelial cells (LECs) proliferation and migration is another vital functional response to hypoxia. EGR-1 has been reported involved in hypoxia-induced lymphangiogenesis via VEGF signaling cascades. However, the underlying molecular mechanism of EGR-1 in lymphangiogenesis still needs further studies. [56]. TNFα is an inflammatory mediator that secreted by macrophagocyte in hypoxic, and then increases EGR-1-transactivated GROα and MMP-9 expression within the tumor microenvironment [57, 58] (Fig. 4).

Fig. 4
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The pathway of EGR-1 in tumor microenvironment

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EGR-1 potentiates tumor treatment

Serum response elements (SRFs), a member of MADS box family, regulates various genes associated with cell growth and differentiation [59]. Deletion analysis provided insights that murine EGR-1 promoter holds two regions that kept two SREs. CArG element is the core of SREs [60]. Studies exhibited that up-regulation of EGR-1 by X-rays was conferred by CArG elements. Moreover, ROIs facilitated EGR-1 expression via activating CArG elements [61]. Seung LP and his companions ligated the CArG elements from EGR-1 promoter to the transcriptional start site of the human TNF cDNA and then this construct was transfected into tumor cell lines via cationic liposomes. Results showed, together with ionizing radiation or anticancer drugs, this genetic radiotherapy or chemo-inducible gene therapy could overcome tumor resistance to cytotoxic agents [62, 63]. Analogously, combination of hypoxia responsive elements (HREs) from the erythropoietin (EPO) and CArG elements from EGR-1 formed a novel chimeric gene promoter. Using such chimeric promoter may effectively address the problem of hypoxia in radiotherapy in cancer cells [64]. Wang WD constructed a special adenoviral vector including CArG elements and the upstream of the human wt-p53 gene. An enhanced antitumor response has been detected in the human NSCLC cells xenografts mice when treatment with AdEgr-p53 and cisplatin synchronously [65].

In conclusion, studies confirmed the potential antineoplastic effects of gene therapy vectors. Synergistically with radiation therapy and chemotherapy, the vector could achieve better therapeutic effects and lower normal tissues damage. These findings not only lead to a better understanding of the mechanism, but also shed light on the potential new strategy for developing treatment of cancer patients.

Conclusion

A worldwide epidemic of cancer-associated disaster is expected to come. The detection of molecular interaction in tumors may make a new point to the discovery of new therapeutic targets. Activation of EGR-1 is essential in normal cell growth, but the exact role kept on the tumorigenesis is unclear. EGR-1 is the key molecule in many signal pathways, and it is conceivable that some of these hold the tumor-promoting effects, whereas others are used to reduce tumor cells survival. Aberrant expression of EGR-1 seems commonly in a mass of human cancers. Undoubtedly, elucidation of the underlying molecular mechanism of EGR-1 signaling crosstalk and specific regulators will be necessary for effective anticancer strategies.

Our review sets out the case for EGR-1 as “friend” in various visual angles. Primarily, EGR-1 is “the guardian of the genome” in p53-lacked prostate cells via inducing TNFα activation, or cooperates with p53 gene promoting the anticancer efficiency of cisplatin as well as quercentin under the physiologic motion. Besides, EGR-1 potentiates the tumor cells apoptosis via upregulating tumor suppressors, NAG-1 and PTEN directly. Next, EGR-1 could inhibit the growth of tumor stem spheroids under low oxygen tension. Furthermore, EGR-1 augments the anticancer effects of 5FU by the way of TSP-1-mediated anti-angiogenesis in solid tumors. Most notably, the CArG elements located in EGR-1 promoter are essential for the construction of suicide gene vector and increase the radiation and chemotherapy sensitivity in vitro. We also discuss the “foes” manners of EGR-1 that are potent correlated with hostile microenvironment and pro-survival function. As the downstream molecule of MAPK-signaling pathway, EGR-1 could be upregulated by a vast of growth factors in several cancer cells, and then promote the transcriptional activation of cyclinD1 to maintain tumor cells mitosis. Meanwhile, EGR-1 also augments tumor metastasis via EGR-1-induced Slug and Snail expression. In a consistent manner, EGR-1 facilitates HIF-1α-mediated VEGF-A expression or directly activated VEGF-A transcription to enhance the angiogenesis and lymphangiogenesis in intratumoral hypoxia microenvironment. To conclude, EGR-1 is anti-oncogenes that monitor DNA-damage conserving, promotes tumor cells apoptosis, and adjuvant increases anticancer efficiency of radiotherapy and chemotherapy. However, at the hostile environment, the EGR-1 expression level increased to maintain tumor cell survival, proliferation, metastasis and angiogenesis as an oncogene. Identifying and utilizing the “foes” role of EGR-1 in cancer could lead an opening of horizons for the gene treatment in patients with malignant tumors.