Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Philipps University Marburg, Department of Neurosurgery, UKGM Marburg, Baldingerstrasse, 35039, Marburg, Germany.
Biomed Pharmacother. 2018 Jan;97:1066-1077. doi: 10.1016/j.biopha.2017.11.034. Epub 2017 Nov 9.
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.
垂体腺瘤是具有侵袭性的第二大常见原发性脑肿瘤。我们之前已经发现 ADAM12（解整合素和金属蛋白酶 12）的过表达与垂体腺瘤的肿瘤侵袭有关，但是其潜在的机制仍不清楚。本研究旨在阐明 ADAM12 在调节垂体腺瘤肿瘤侵袭中的机制作用。在本研究中，我们首先表明 ADAM12 的表达与人类垂体腺瘤的临床标本中的上皮间质转化（EMT）过程同时发生。进一步的功能研究表明，垂体腺瘤细胞中 ADAM12 的沉默显著抑制了 EMT 过程，并抑制了细胞迁移、侵袭和增殖，而不影响细胞凋亡。在机制上，ADAM12 的沉默显著减少了表皮生长因子受体（EGFR）配体的胞外结构域脱落，并减弱了 EGFR/ERK 信号通路。阻断 EGFR 信号通路可导致 EMT 抑制类似于 ADAM12 的沉默，并减少细胞迁移、侵袭和增殖，而 EGFR 的激活则消除了 ADAM12 沉默对 EMT、增殖、迁移和侵袭的抑制作用。此外，ADAM12 的沉默显著削弱了体内垂体腺瘤细胞的致瘤性和 EMT。总之，我们的研究提供了重要的证据，表明 ADAM12 通过 EGFR/ERK 信号通路诱导 EMT，并促进垂体腺瘤中的细胞迁移、侵袭和增殖。这些发现强烈表明，ADAM12 可能成为垂体腺瘤的一个新的有价值的治疗靶点。
