Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation

• Published in: Cancers Vol. 10; no. 6; p. 190
• Main Authors: Yamasaki, Koji, Mukai, Shoichiro, Sugie, Satoru, Nagai, Takahiro, Nakahara, Kozue, Kamibeppu, Toyoharu, Sakamoto, Hiromasa, Shibasaki, Noboru, Terada, Naoki, Toda, Yoshinobu, Kataoka, Hiroaki, Kamoto, Toshiyuki
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.06.2018; MDPI
• Subjects: Bone cancer; Bone growth; Bone imaging; c-Met protein; Gene expression; Growth factors; Hepatocyte growth factor; Invasiveness; Kidney cancer; Kinases; Ligands; Medical prognosis; Metastases; Metastasis; Motility; Patients; Phosphorylation; Renal cell carcinoma; Urology; Ventricle; Japan; HAI-2; RCC; bone metastasis; MET; HGF
• ISSN: 2072-6694; 2072-6694
• 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.