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Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone
Metastasis through Ligand-Dependent MET Phosphorylation
#MMPMID29890660
Yamasaki K
; Mukai S
; Sugie S
; Nagai T
; Nakahara K
; Kamibeppu T
; Sakamoto H
; Shibasaki N
; Terada N
; Toda Y
; Kataoka H
; Kamoto T
Cancers (Basel)
2018[Jun]; 10
(6
): ? PMID29890660
show ga
MET, a c-met 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.
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