ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway
ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway
复制标题
ADAM12通过EGFR/ERK信号通路诱导垂体腺瘤EMT并促进细胞迁移、侵袭和增殖
DOI：
10.1016/j.biopha.2017.11.034
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发表时间：
2018-01-01
影响因子：
7.5
通讯作者：
Lei, Ting
中科院分区：
文献类型：
--
作者：
Wang, Junwen;Zhang, Zhuo;Lei, Ting
垂体腺瘤是第二常见的具有侵袭性的原发性脑肿瘤。我们以前发现，ADAM 12（解整合素和金属蛋白酶12）的过度表达与垂体腺瘤的肿瘤侵袭，但其潜在的机制仍然未知。本研究旨在阐明ADAM 12在调节垂体腺瘤侵袭中的作用机制。在本研究中，我们首次发现，在人类垂体腺瘤的临床标本中，ADAM 12的表达伴随着上皮间质转化（EMT）过程。进一步的功能研究表明，ADAM 12基因沉默可显著抑制垂体腺瘤细胞的EMT过程，抑制细胞的迁移、侵袭和增殖，但不影响细胞凋亡。从机制上讲，ADAM 12沉默显著减少了表皮生长因子受体（EGFR）配体的胞外域脱落，并减弱了EGFR/ERK信号通路。阻断EGFR信号通路可抑制EMT的发生，并降低细胞的迁移、侵袭和增殖能力，而EGFR激活则可消除ADAM 12沉默对EMT、增殖、迁移和侵袭的抑制作用。此外，ADAM 12沉默显着损害垂体腺瘤细胞在体内的肿瘤发生和EMT。综上所述，我们的研究为ADAM 12通过EGFR/ERK信号通路诱导垂体腺瘤EMT并促进细胞迁移、侵袭和增殖提供了重要证据。这些发现有力地表明，ADAM 12可能作为一个新的有价值的治疗垂体腺瘤的目标。
Pituitary adenomas are the second most common primary brain tumor with invasive properties. We have previously identified that ADAM12 (a disintegrin and metalloprotease 12) overexpression is associated with the tumor invasion of pituitary adenomas, however, the underlying mechanism remains unknown. This study aims to elucidate the mechanistic role of ADAM12 in regulating the tumor invasion of pituitary adenomas. In this study, we first showed that ADAM12 expression was concomitant with epithelial to mesenchymal transition (EMT) process in clinical specimens of human pituitary adenomas. Further functional studies showed that ADAM12 silencing in pituitary adenoma cells significantly inhibited the EMT process and suppressed cell migration, invasion and proliferation without influencing cell apoptosis. Mechanistically, ADAM12 silencing significantly reduced ectodomain shedding of epidermal growth factor receptor (EGFR) ligands and attenuated the EGFR/ERK signaling pathway. Blocking of EGFR signaling resulted in EMT suppression similar to silencing of ADAM12 and reduced cell migration, invasion and proliferation, while EGFR activation abolished the suppression on EMT, proliferation, migration and invasion induced by ADAM12 silencing. Moreover, ADAM12 silencing significantly impaired tumorigenesis and EMT of pituitary adenoma cells in vivo. Taken together, our study provide crucial evidence that ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway. These finds strongly suggest that ADAM12 might serve as a novel valuable therapeutic target for pituitary adenomas.