Department of Thyroid and Mammary Gland Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Department of Breast Surgery, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China.
J Cell Biochem. 2020 Oct;121(10):4142-4153. doi: 10.1002/jcb.29666. Epub 2020 Feb 12.
Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a tyrosine-protein kinase receptor highly implicated in the growth plate and cartilage development, which may be involved in epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells. Although ROR2 is known to promote the migration of BC cells, the detailed mechanism of this event is still not clear. Here, we found that ROR2 expression was significantly increased in BC lymphatic metastatic tissue as well as BC samples compared to normal adjacent breast tissues. A higher expression of ROR2 in MDA-MB-231 and a lower expression of ROR2 in MCF-7 cells were observed. MDA-MB-231-siROR2 cells with ROR2 knockdown inhibited MDA-MB-231 cell invasion, migration, and clonal formation, while MCF-7-OvROR2 cells with overexpression showed the opposite results. The underlying mechanisms involved in ROR2-induced EMT in MDA-MB-231 and MCF-7 cells were further investigated. ROR2 may activate EMT progression in BC cells by altering MAPK kinase 3/6 (MKK3/6) expression. The expressions of transforming growth factor-β, matrix metalloproteinase-2 (MMP-2), and MMP-9, which were related to tumor cell invasion activities, were notably increased in MCF-7-OvROR2 cells. The EMT markers, including snail, N-cadherin, tissue inhibitor of metalloproteinases-1, and vimentin, were significantly upregulated in MCF-7-OvROR2 cells. On the contrary, E-cadherin was obviously reduced expressed in MCF-7-OvROR2 cells. ROR2 may regulate the malignant phenotype of BC cells possibly via activation of mitogen-activated protein kinase (MAPK)/p38 signaling pathway. Collectively, ROR2 promotes BC carcinogenesis by mediating the MAPK/p38 pathway, which is independent of Wnt5α.
受体酪氨酸激酶样孤儿受体 2（ROR2）是一种酪氨酸蛋白激酶受体，在生长板和软骨发育中高度表达，可能参与乳腺癌（BC）细胞的上皮-间充质转化（EMT）。尽管已知 ROR2 促进 BC 细胞的迁移，但该事件的详细机制尚不清楚。在这里，我们发现 ROR2 在 BC 淋巴转移组织以及 BC 样本中的表达明显高于正常相邻乳腺组织。在 MDA-MB-231 细胞中观察到 ROR2 的高表达，而在 MCF-7 细胞中 ROR2 的表达较低。用 ROR2 敲低的 MDA-MB-231-siROR2 细胞抑制 MDA-MB-231 细胞侵袭、迁移和克隆形成，而过表达 ROR2 的 MCF-7-OvROR2 细胞则表现出相反的结果。进一步研究了 ROR2 在 MDA-MB-231 和 MCF-7 细胞中诱导 EMT 的潜在机制。ROR2 可能通过改变丝裂原活化蛋白激酶激酶 3/6（MKK3/6）的表达来激活 BC 细胞中的 EMT 进程。转化生长因子-β、基质金属蛋白酶-2（MMP-2）和 MMP-9 的表达，这些与肿瘤细胞侵袭活性相关的因子，在 MCF-7-OvROR2 细胞中明显增加。EMT 标志物，包括 snail、N-钙粘蛋白、金属蛋白酶组织抑制剂-1 和波形蛋白，在 MCF-7-OvROR2 细胞中明显上调。相反，E-钙粘蛋白在 MCF-7-OvROR2 细胞中明显减少表达。ROR2 可能通过激活丝裂原活化蛋白激酶（MAPK）/p38 信号通路来调节 BC 细胞的恶性表型。总之，ROR2 通过调节 MAPK/p38 通路促进 BC 癌变，这与 Wnt5α 无关。
