Collagen triple helix repeat containing 1 (CTHRC1) activates Integrin β3/FAK signaling and promotes metastasis in ovarian cancer.
Collagen triple helix repeat containing 1 (CTHRC1) activates Integrin β3/FAK signaling and promotes metastasis in ovarian cancer.
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含有 1 (CTHRC1) 的胶原蛋白三螺旋重复序列激活整合素 β3/FAK 信号传导并促进卵巢癌转移
DOI：
10.1186/s13048-017-0358-8
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发表时间：
2017-10-11
影响因子：
4
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Guo B;Yan H;Li L;Yin K;Ji F;Zhang S
背景转移是上皮性卵巢癌（epithelial ovarian cancer，EOC）患者发病和死亡的主要原因，但其发生机制尚不清楚。CTHRC 1是一种分子量为28-kDa的分泌型蛋白质，参与血管重塑、骨形成和形态发生。本研究旨在探讨CTHRC 1在卵巢上皮性癌转移中的作用及其分子机制。方法通过体内外实验验证CTHRC 1在卵巢上皮性癌转移中的生物学功能。采用荧光抗体芯片技术和免疫共沉淀技术检测和鉴定整合素β3/FAK信号通路介导CTHRC 1的功能。分析了72例EOC标本中CTHRC 1/integrin β3的表达与患者临床病理特征之间的关系。ResultsWe证明CTHRC 1增强了EOC的生物学行为，包括细胞迁移、侵袭以及体外与细胞-细胞外基质的粘附能力。此外，CTHRC 1在腹膜内卵巢异种移植模型中促进EOC细胞的转移性扩散，并且这种表型主要归因于整合素/FAK信号传导的激活。从机制上讲，我们确定FAK在Tyr 397上磷酸化，并被整合素β3激活，这对CTHRC 1介导的EOC细胞体外迁移和侵袭能力以及腹膜内转移很重要。此外，我们发现CTHRC 1/整合素β3表达减弱预测预后不良的表型和晚期临床分期的EOC.ConclusionsOur结果表明，CTHRC 1，一个新发现的调节器的IP转移通过激活整合素β3/FAK信号在EOC中，可能是一个潜在的治疗靶点卵巢癌。
BackgroundMetastasis is the major cause of morbidity and mortality in patients with epithelial ovarian cancer (EOC), however the mechanisms that underline this process are poorly understood. Collagen triple helix repeat containing-1 (CTHRC1) is a 28-kDa secreted protein reported to be involved in vascular remodeling, bone formation and morphogenesis. This study aimed to investigate the role of CTHRC1 in promoting the metastasis of EOC and to elucidate the underlying molecular mechanisms.MethodsThe biologic functions of CTHRC1 in metastasis were validated both in vivo and in vitro experiments. The phosphor-antibody microarray analysis and Co-immunoprecipitation were performed to detect and identify the integrin β3/FAK signaling pathway that mediated the function of CTHRC1. Seventy two EOC samples were analyzed for association between CTHRC1/integrin β3 expression and patient clinicopathological features.ResultsWe demonstrated that CTHRC1 enhances the biological behavior of EOC including cell migration, invasion, as well as its adhesion capability to cell-extracellular matrix in vitro. Additionally, CTHRC1 promoted metastatic spread of EOC cells in an i.p. ovarian xenograft model and this phenotype was primarily ascribed to the activation of integrin/FAK signaling. Mechanistically, we determined that FAK were phosphorylated on Tyr397, and were activated by integrin β3, which is important for the CTHRC1-mediated migratory and invasive ability of EOC cells in vitro and i.p. metastasis. In addition, we found that attenuated CTHRC1/integrin β3 expression predicted a poor prognostic phenotype and advanced clinical stage of EOC.ConclusionsOur results suggest that CTHRC1, a newly identified regulator of i.p. metastasis through activation of integrin β3/FAK signaling in EOC, may represent a potential therapeutic target for ovarian cancer.
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影响因子：
--
作者：
Spina A;Di Maiolo F;Esposito A;Sapio L;Chiosi E;Sorvillo L;Naviglio S
通讯作者：
Naviglio S
影响因子：
--
作者：
Sawada K;Ohyagi-Hara C;Kimura T;Morishige K
通讯作者：
Morishige K
DOI：
10.1083/jcb.201501025
发表时间：
2015-08-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim NG;Gumbiner BM
通讯作者：
Gumbiner BM
影响因子：
37.3
作者：
Salvo E;Garasa S;Dotor J;Morales X;Peláez R;Altevogt P;Rouzaut A
通讯作者：
Rouzaut A
影响因子：
4.8
作者：
Slack-Davis, Jill K.;Martin, Karen H.;Parsons, J. Thomas
通讯作者：
Parsons, J. Thomas