Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, QC.
Blood. 2010 Aug 5;116(5):759-66. doi: 10.1182/blood-2009-12-257030. Epub 2010 May 14.
Progression of hematologic malignancies is strongly dependent on bidirectional interactions between tumor cells and stromal cells. Expression of members of the matrix metalloproteinase (MMP) family by stromal cells is a central event during these interactions. However, although several studies have focused on the mechanisms responsible for induction of MMP in stromal cells, the signals that negatively regulate their secretion of in these cells remain largely unknown. Here, we provide evidence that MMP-9 production by stromal cells is suppressed through activation of early growth response protein 1 (EGR-1), thereby inhibiting the growth of thymic lymphoma. We found that EGR-1 expression is induced in stromal cells after contact with lymphoma cells via epidermal growth factor (EGF). Moreover, development of thymic lymphoma was inhibited when induced by lymphoma cells overexpressing EGF compared with control lymphoma cells. Using transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome, we further demonstrated that EGF/EGR-1 repressed transcriptional activation of the MMP-9 gene by stromal cells. De novo expression of EGR-1 alone by gene transfer or exposure to recombinant human EGF also inhibited MMP-9 expression. Taken together, these results indicate that EGR-1 could be a source of novel targets for therapeutic intervention in lymphoid tumors in which MMP-9 plays a critical role.
血液恶性肿瘤的进展强烈依赖于肿瘤细胞和基质细胞之间的双向相互作用。基质细胞中细胞外基质金属蛋白酶（MMP）家族成员的表达是这些相互作用中的一个核心事件。然而，尽管有几项研究集中在诱导基质细胞中 MMP 表达的机制上，但对负调控这些细胞中 MMP 分泌的信号仍知之甚少。在这里，我们提供的证据表明，基质细胞中 MMP-9 的产生受到早期生长反应蛋白 1（EGR-1）的激活的抑制，从而抑制了胸腺癌的生长。我们发现，通过表皮生长因子（EGF）与淋巴瘤细胞接触后，基质细胞中 EGR-1 的表达被诱导。此外，与对照淋巴瘤细胞相比，过表达 EGF 的淋巴瘤细胞诱导时，胸腺癌的发展受到抑制。通过在其基因组中含有 MMP-9 启动子驱动的荧光素酶转基因的转基因小鼠，我们进一步证明 EGF/EGR-1 抑制了基质细胞对 MMP-9 基因的转录激活。通过基因转移或暴露于重组人 EGF 单独表达 EGR-1 也抑制了 MMP-9 的表达。总之，这些结果表明 EGR-1 可能成为在 MMP-9 发挥关键作用的淋巴肿瘤中治疗干预的新靶点。
