ERM/ETV5 up-regulation plays a role during myometrial infiltration through matrix metalloproteinase-2 in endometrial cancer
ERM/ETV5 up-regulation plays a role during myometrial infiltration through matrix metalloproteinase-2 in endometrial cancer
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DOI：
10.1158/0008-5472.can-06-4487
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Abal, Miguel
中科院分区：
文献类型：
--
作者：
Monge, Marta;Colas, Eva;Abal, Miguel
我们最近描述了Ets家族转录因子ERM/ETV5在子宫内膜样子宫内膜癌（EEC）中特异性上调，并与子宫肌层浸润相关。Ets家族成员通过上调基质降解蛋白酶的表达与肿瘤进展相关。在本研究中，我们研究了在EEC中，ERM/ETV5可能通过诱导参与细胞外基质重塑的基因表达而起作用。揭示与肿瘤侵袭起始相关的分子事件将代表EEC患者的明显改善。ERM/ETV5在子宫内膜癌细胞系Hec-1A中过度表达诱导散射，与基质金属蛋白酶-2 （MMP-2）明胶酶活性升高相关。染色质免疫沉淀和RNA干扰和特异性MMP-2抑制剂的还原实验表明，ERM/ETV5过表达与MMP-2激活之间存在功能联系。在小鼠模型中，与ERM/ETV5过表达相关的MMP-2活性增加赋予子宫内膜肿瘤侵袭能力。原位植入的过表达ERM/ETV5肿瘤表现出更强的侵袭性和浸润性。最后，ERM/ETV5和MMP-2在浸润性人子宫内膜癌子宫肌层浸润前的特异性定位进一步强化了ERM/ETV5在子宫内膜传播早期阶段发挥作用的假设。综上所述，这些结果使我们提出，在EEC中，ERM/ETV5通过MMP-2明胶溶解活性发挥作用，赋予侵袭能力，并与肌层浸润的初始转换有关。他们还假设ERM/ETV5是患者分层的有价值的标记物，也是一种转录途径，应该对针对EEC传播初始阶段的治疗进行评估。
We have described recently the Ets family transcription factor, ERM/ETV5, specifically up-regulated in endometrioid endometrial carcinoma (EEC) and associated with myometrial infiltration. Ets family members have been correlated to tumor progression by up-regulating the expression of matrix-degrading proteases. In the present study, we investigated the possibility that in EEC, ERM/ETV5 may act by inducing the expression of genes involved in extracellular matrix remodeling. Unraveling the molecular events associated with the initiation of tumor invasion would represent an obvious improvement for EEC patients. The overexpression of ERM/ETV5 induced scattering in the endometrial cancer cell line Hec-1A, correlating to increased matrix metalloproteinase-2 (MMP-2) gelatinase activity. Both chromatin immunoprecipitation and reversion experiments with RNA interference and specific MMP-2 inhibitor showed a functional link between ERM/ETV5 overexpression and MMP-2 activation. The increased MMP-2 activity associated with overexpressed ERM/ETV5 in a mouse model conferred invasive capacity to endometrial tumors. Orthotopically implanted overexpressing ERM/ETV5 tumors presented a more aggressive and infiltrative pattern of myometrial invasion. Finally, the specific localization of ERM/ETV5 and MMP-2 at the invasive front of myometrial infiltrating human endometrial carcinomas further reinforced the hypothesis of a role for ERM/ETV5 in the early steps of endometrial dissemination. Taken together, these results lead us to propose that in EEC, ERM/ETV5 acts through MMP-2 gelatinolytic activity to confer invasive capabilities, associated with an initial switch to myometrial infiltration. They also postulate ERM/ETV5 as a valuable marker for patient stratification and a transcription pathway that should be evaluated for therapies specifically targeting the initial steps of EEC dissemination.