EGR1 regulates angiogenic and osteoclastogenic factors in prostate cancer and promotes metastasis
EGR1 regulates angiogenic and osteoclastogenic factors in prostate cancer and promotes metastasis
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EGR1调节前列腺癌中的血管生成和破骨细胞生成因子并促进转移
DOI：
10.1038/s41388-019-0873-8
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发表时间：
2019-08-29
期刊：
影响因子：
8
通讯作者：
Kelly, Kathleen
中科院分区：
文献类型：
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作者：
Li, Lechen;Ameri, Amir H.;Kelly, Kathleen
早期生长反应-1（EGR 1）是一种在多种情况下与前列腺癌（PC）进展相关的转录因子。例如，EGR 1水平的增加是由于雄激素受体信号传导受到抑制或肿瘤抑制因子PTEN的缺失。EGR 1已被证明调节影响增殖、凋亡、免疫细胞活化和基质降解等的基因。尽管如此，EGFR 1对PC转移定植的影响尚不清楚。我们使用骨和脑转移的PC模型（DU 145/RasB 1）证明EGR 1表达调节转移瘤的血管生成和破骨细胞生成特性。我们先前已经表明，在该模型中，FN 14（TNFRSF 12 A）和下游NF-κB信号传导是转移所必需的。我们发现FN 14连接也导致NF-κ B非依赖性、MEK依赖性的EGFR 1表达，DU 145/RasB 1细胞中EGFR 1缺失减少了转移灶的数量和大小，但不影响原发肿瘤的生长。EGR 1表达降低导致脑血管密度降低和骨转移，以及溶骨性骨病变面积减少和骨肿瘤界面破骨细胞数量减少。TWEAK（TNFSF 12）诱导了几种EGFR 1依赖性血管生成和破骨细胞生成因子（例如，PDGFA、TGFB 1、SPP 1、IL 6、IL 8和TGFA等）。与此一致，在PC的临床样本中，编码血管生成/破骨细胞生成途径效应物的几种基因的水平与EGFR 1水平相关。因此，我们在这里表明EGR 1对前列腺癌转移有直接影响。EGR 1调节血管生成和破骨细胞生成因子，为影响癌症转移的自主和微环境机制的潜在信号网络提供信息。
Early growth response-1 (EGR1) is a transcription factor correlated with prostate cancer (PC) progression in a variety of contexts. For example,EGR1levels increase in response to suppressed androgen receptor signaling or loss of the tumor suppressor,PTEN. EGR1has been shown to regulate genes influencing proliferation, apoptosis, immune cell activation, and matrix degradation, among others. Despite this, the impact ofEGR1on PC metastatic colonization is unclear. We demonstrate using a PC model (DU145/RasB1) of bone and brain metastasis thatEGR1expression regulates angiogenic and osteoclastogenic properties of metastases. We have shown previously that FN14 (TNFRSF12A) and downstream NF-κB signaling is required for metastasis in this model. Here we demonstrate that FN14 ligation also leads to NF-κB-independent, MEK-dependentEGR1expression.EGR1-depletion in DU145/RasB1 cells reduced both the number and size of metastases but did not affect primary tumor growth. DecreasedEGR1expression led to reduced blood vessel density in brain and bone metastases as well as decreased osteolytic bone lesion area and reduced numbers of osteoclasts at the bone–tumor interface. TWEAK (TNFSF12) induced severalEGR1-dependent angiogenic and osteoclastogenic factors (e.g., PDGFA, TGFB1, SPP1, IL6, IL8, and TGFA, among others). Consistent with this, in clinical samples of PC, the level of several genes encoding angiogenic/osteoclastogenic pathway effectors correlated withEGR1levels. Thus, we show here thatEGR1has a direct effect on prostate cancer metastases. EGR1 regulates angiogenic and osteoclastogenic factors, informing the underlying signaling networks that impact autonomous and microenvironmental mechanisms of cancer metastases.