Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation.
Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation.
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DOI：
10.3390/cancers10060190
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发表时间：
2018-06-08
期刊：
影响因子：
5.2
通讯作者：
Kamoto T
中科院分区：
文献类型：
--
作者：
Yamasaki K;Mukai S;Sugie S;Nagai T;Nakahara K;Kamibeppu T;Sakamoto H;Shibasaki N;Terada N;Toda Y;Kataoka H;Kamoto T
MET是一种c-met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。在以前的研究中，我们报道了MET和间质蛋白酶（一种新型的HGF激活剂）在骨转移中的表达增加。在这项研究中，我们采用了肾细胞癌（RCC）骨转移的小鼠模型，以阐明HGF/MET信号轴和HGF激活抑制剂2型（HAI-2）的调节剂的意义。将荧光素酶转染的786-O细胞注射到小鼠左心室中以制备小鼠骨转移模型。通过全身生物发光成像证实骨转移的形成，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稳定敲减的786-O细胞，并分析了侵袭性和运动性。骨转移灶中HGF和matriptase的表达较对照组增加，而HAI-2的表达较对照组减少。此外，我们证实了骨转移中MET的磷酸化增加。通过敲低HAI-2，间质蛋白酶的表达上调，侵袭性和运动性均显著增加。配体依赖性MET活化在RCC骨转移中的意义被认为是重要的，HAI-2可能是该系统中的重要调节剂。
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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影响因子：
3.3
作者：
Giubellino A;Linehan WM;Bottaro DP
通讯作者：
Bottaro DP
DOI：
10.1158/1541-7786.mcr-12-0071
发表时间：
2012-08
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Najy AJ;Won JJ;Movilla LS;Kim HR
通讯作者：
Kim HR
影响因子：
2.1
作者：
Knudsen, BS;Gmyrek, GA;Woude, GFV
通讯作者：
Woude, GFV
影响因子：
21.3
作者：
Joffre, Carine;Barrow, Rachel;Kermorgant, Stephanie
通讯作者：
Kermorgant, Stephanie
影响因子：
45.3
作者：
Rini, Brian I.;Wilding, George;Dutcher, Janice P.
通讯作者：
Dutcher, Janice P.