Functional and therapeutic relevance of hepatocyte growth factor/c-MET signaling in synovial sarcoma.
Functional and therapeutic relevance of hepatocyte growth factor/c-MET signaling in synovial sarcoma.
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DOI：
10.1111/cas.13092
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发表时间：
2016-12
期刊：
影响因子：
5.7
通讯作者：
Naka N
中科院分区：
文献类型：
--
作者：
Imura Y;Nakai T;Yamada S;Outani H;Takenaka S;Hamada K;Araki N;Itoh K;Yoshikawa H;Naka N
滑膜肉瘤（SS）是一种侵袭性的软组织肉瘤，预后差，因此，迫切需要新的治疗策略。在本研究中，我们研究了肝细胞生长因子（HGF）/c-MET信号在SS中的功能和治疗相关性。HGF和c-MET均在Yamato-SS细胞中高度表达，导致c-MET及其下游AKT和细胞外信号调节激酶信号通路的激活，而c-MET在SYO-1或HS-SY-II细胞中表达但不激活。与c-MET-灭活的SYO-1或HS-SY-II细胞相比，c-MET-活化的Yamato-SS细胞显示出更高的锚定非依赖性生长能力和更低的化疗药物敏感性。选择性c-MET抑制剂INC 280在体外和体内均抑制Yamato-SS细胞的生长，但不抑制SYO-1或HS-SY-II细胞的生长。INC 280诱导细胞周期停滞和凋亡，并阻断Yamato-SS细胞中c-MET及其下游效应物的磷酸化。SS临床样本中HGF和c-MET的共表达与SS患者的不良预后相关。总之，HGF/c-MET信号以自分泌方式激活导致SS的侵袭性表型，靶向该信号对c-MET激活的SS发挥上级抗肿瘤作用。HGF/c-MET表达状态是一种潜在的生物标志物，用于识别预后较差的SS患者，这些患者可以从c-MET抑制剂中获益。
Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with a poor prognosis and, thus, novel therapeutic strategies for SS are urgently required. In the present study, we investigated the functional and therapeutic relevance of hepatocyte growth factor (HGF)/c‐MET signaling in SS. Both HGF and c‐MET were highly expressed in Yamato‐SS cells, resulting in activation of c‐MET and its downstream AKT and extracellular signal‐regulated kinase signaling pathways, whereas c‐MET was expressed but not activated in SYO‐1 or HS‐SY‐II cells. c‐MET‐activated Yamato‐SS cells showed higher anchorage‐independent growth ability and less sensitivity to chemotherapeutic agents than did c‐MET‐inactivated SYO‐1 or HS‐SY‐II cells. INC280, a selective c‐MET inhibitor, inhibited growth of Yamato‐SS cells both in vitro and in vivo but not that of SYO‐1 or HS‐SY‐II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c‐MET and its downstream effectors in Yamato‐SS cells. Co‐expression of HGF and c‐MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c‐MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c‐MET‐activated SS. HGF/c‐MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c‐MET inhibitors.
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影响因子：
5.2
作者：
Kawaguchi M;Kataoka H
通讯作者：
Kataoka H
DOI：
10.1016/j.bbrc.2014.01.084
发表时间：
2014-02-28
影响因子：
3.1
作者：
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通讯作者：
Shim, Kwang Yong
影响因子：
20.3
作者：
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通讯作者：
Tanavde, Vivek
影响因子：
9.7
作者：
Kawai, A;Naito, N;Beppu, Y
通讯作者：
Beppu, Y
影响因子：
5.2
作者：
Naka, Norifumi;Takenaka, Satoshi;Itoh, Kazuyuki
通讯作者：
Itoh, Kazuyuki