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

Abstract

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...

Early Growth Response 1-Dependent Downregulation of Matrix Metalloproteinase 9 and Mouse Double Minute 2 Attenuates Head and Neck Squamous Cell Carcinoma Metastasis

“…EGR1 has been reported to promote MMP9 expression in HeLa cell [11]. However, in lymphoma, EGR1 inhibits MMP9 expression by direct promoter binding [12]. Our data showed that exogenous EGR1 overexpression inhibited mRNA and protein expression of MMP9, which is consistent with the result in lymphoma.…”

“…Previous study showed that EGR1 inhibits MMP2 expression by direct promoter binding in human breast cancer cell [10]. EGR1 has been reported to promote MMP9 expression in HeLa cells [11], but to inhibit its expression in lymphoma [12]. It has been known that MDM2 promotes metastasis of breast cancer by upregulating MMP9 [13].…”

α2β1 Integrin Promotes Chemoresistance against Doxorubicin in Cancer Cells through Extracellular Signal-regulated Kinase (ERK)

“…ECM remodeling and degradation by metalloproteinases, which is associated with cancer growth and invasion, is likely to lead to the release of ECM components that can act as "soluble" pep- tides within the tumor microenvironment. T cell malignancies are also associated with metalloproteinases and ECM remodeling as well as dissemination (41)(42)(43)(44). Thus, our study suggests that the ColI released from tissue ECM can bind to ␣2␤1 integrin and provides T-ALL cells with a survival advantage against the cytotoxic effect of doxorubicin.…”

Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors

“…Furthermore, there were several interesting genes involved in the transcriptional misregulation of cancer, such as Runx2 , Mmp3 , Mmp9 , Egln3 and Vegfa . [80–83] We also found upregulation of the Id2 transcript in iNKT tumors as compared to premalignant iNKT cells (Figure 8B). This could represent overexpression of Id2 exon 3, which is the only remaining exon in Id2 f/f mice.…”