Solid tumors start as a local disease, but some are capable of metastasizing to the lymph nodes and distant organs. The hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating cancer progression and metastasis. However, the molecular mechanisms mediating the disseminated cancer cell metastasis remain incompletely understood. Here, we show that C/EBPβ/AEP signaling that is upregulated in breast cancers mediates oxidative stress and lung metastasis, and inactivation of asparagine endopeptidase (AEP, also known as legumain) robustly regulates breast cancer reactive oxygen species (ROS) and metastasis. AEP, a protease activated in acidic conditions, is overexpressed in numerous types of cancer and promotes metastasis. Employing a breast cancer cell line MDA-MD-231, we show that C/EBPβ, an oxidative stress or inflammation-activated transcription factor, and its downstream target AEP mediate ROS production as well as migration and invasion in cancer cells. Deficiency of AEP in the MMTV-PyMT transgenic breast cancer mouse model significantly regulates oxidative stress and suppresses lung metastasis. Administration of an innovative AEP inhibitor substantially mitigates ROS production and cancer metastasis. Hence, our study demonstrates that pharmacologic inhibition of AEP activity might provide a disease-modifying strategy to suppress cancer metastasis.

中文翻译：

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C/EBP{beta}/AEP 信号传导调节恶性肿瘤中的氧化应激，刺激转移

实体瘤最初是一种局部疾病，但有些能够转移到淋巴结和远处器官。在癌症发展过程中至关重要的低氧微环境在调节癌症进展和转移中起着关键作用。然而，介导播散性癌细胞转移的分子机制仍不完全清楚。在这里，我们表明在乳腺癌中上调的 C/EBPβ/AEP 信号传导介导氧化应激和肺转移，而天冬酰胺内肽酶 (AEP，也称为legumain) 的失活强有力地调节乳腺癌活性氧 (ROS) 和转移。AEP 是一种在酸性条件下激活的蛋白酶，在多种癌症中过度表达并促进转移。使用乳腺癌细胞系 MDA-MD-231，我们显示 C/EBPβ，一种氧化应激或炎症激活的转录因子，其下游靶标 AEP 介导 ROS 的产生以及癌细胞中的迁移和侵袭。MMTV-PyMT 转基因乳腺癌小鼠模型中 AEP 的缺乏显着调节氧化应激并抑制肺转移。施用创新的 AEP 抑制剂可显着减轻 ROS 的产生和癌症转移。因此，我们的研究表明，AEP 活性的药理学抑制可能提供一种疾病缓解策略来抑制癌症转移。MMTV-PyMT 转基因乳腺癌小鼠模型中 AEP 的缺乏显着调节氧化应激并抑制肺转移。施用创新的 AEP 抑制剂可显着减轻 ROS 的产生和癌症转移。因此，我们的研究表明，AEP 活性的药理学抑制可能提供一种疾病缓解策略来抑制癌症转移。MMTV-PyMT 转基因乳腺癌小鼠模型中 AEP 的缺乏显着调节氧化应激并抑制肺转移。施用创新的 AEP 抑制剂可显着减轻 ROS 的产生和癌症转移。因此，我们的研究表明，AEP 活性的药理学抑制可能提供一种疾病缓解策略来抑制癌症转移。