Yamasaki Koji, Mukai Shoichiro, Sugie Satoru, Nagai Takahiro, Nakahara Kozue, Kamibeppu Toyoharu, Sakamoto Hiromasa, Shibasaki Noboru, Terada Naoki, Toda Yoshinobu, Kataoka Hiroaki, Kamoto Toshiyuki
Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Department of Urology, Faculty of Medicine, University of Kyoto, Kyoto 606-8507, Japan.
Cancers (Basel). 2018 Jun 8;10(6):190. doi: 10.3390/cancers10060190.
MET, a proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone metastasis. In this study, we employed a mouse model of renal cell carcinoma (RCC) bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis. The formation of bone metastasis was confirmed by whole-body bioluminescent imaging, and specimens were extracted. Expression of HGF/MET-related molecules was analyzed. Based on the results, we produced HAI-2 stable knockdown 786-O cells, and analyzed invasiveness and motility. Expression of HGF and matriptase was increased in bone metastasis compared with the control, while that of HAI-2 was decreased. Furthermore, we confirmed increased phosphorylation of MET in bone metastasis. The expression of matriptase was upregulated, and both invasiveness and motility were increased significantly by knockdown of HAI-2. The significance of ligand-dependent MET activation in RCC bone metastasis is considered, and HAI-2 may be an important regulator in this system.
MET作为一种原癌基因产物和肝细胞生长因子（HGF）受体，已知在癌症进展（包括骨转移）中发挥重要作用。在先前的一项研究中，我们报道了在骨转移中MET和HGF的一种新型激活剂——matriptase的表达增加。在本研究中，我们采用肾细胞癌（RCC）骨转移小鼠模型来阐明HGF/MET信号轴和HGF激活剂抑制剂2型（HAI-2）的调节作用。将荧光素酶转染的786-O细胞注射到小鼠左心室以制备骨转移小鼠模型。通过全身生物发光成像确认骨转移的形成，并提取标本。分析HGF/MET相关分子的表达。基于这些结果，我们制备了HAI-2稳定敲低的786-O细胞，并分析其侵袭性和运动性。与对照组相比，骨转移中HGF和matriptase的表达增加，而HAI-2的表达降低。此外，我们证实骨转移中MET的磷酸化增加。matriptase的表达上调，并且通过敲低HAI-2，侵袭性和运动性均显著增加。我们考虑了配体依赖性MET激活在RCC骨转移中的意义，并且HAI-2可能是该系统中的一个重要调节因子。
