FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer
FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer
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DOI：
10.1038/s41389-020-0190-7
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发表时间：
2020-02-06
期刊：
影响因子：
6.2
通讯作者：
Natsugoe, Shoji
中科院分区：
文献类型：
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作者：
Hirano, Takuro;Shinsato, Yoshinari;Natsugoe, Shoji
考虑到大多数晚期癌症预后不良，预防侵袭和转移是疾病控制的关键。Ras同源（Rho）鸟嘌呤交换因子（GEFs）及其信号级联可能是晚期癌症的潜在治疗靶点。我们对Cancer Genome Atlas表达数据进行了计算机分析，以确定在晚期胃癌中表达异常的候选Rho- gef基因，发现FERM、Rho/ArhGEF和pleckstrin domain protein 1 （FARP1）表达与预后不良有关。对91例临床晚期胃癌患者预后及病理因素与FARP1免疫组化表达的关系分析显示，FARP1高表达与患者淋巴浸润、淋巴转移及预后不良有显著相关性（P = 0.025）。在胃癌细胞中，FARP1的敲低降低了细胞的运动，而FARP1的过表达通过激活CDC42促进了细胞的运动和丝足的形成。FARP1与整合素β 5相互作用，一种有效的整合素α v β 5抑制剂（SB273005）仅在FARP1高表达的胃癌细胞中阻止细胞运动。这些结果表明，整合素α v β 5-FARP1-CDC42轴在胃癌细胞迁移和侵袭中起着至关重要的作用。因此，Rho上游的调控级联可能是晚期癌症治疗的一个特异性和有希望的靶点。
Considering the poor prognosis of most advanced cancers, prevention of invasion and metastasis is essential for disease control. Ras homologous (Rho) guanine exchange factors (GEFs) and their signaling cascade could be potential therapeutic targets in advanced cancers. We conducted in silico analyses of The Cancer Genome Atlas expression data to identify candidate Rho-GEF genes showing aberrant expression in advanced gastric cancer and found FERM, Rho/ArhGEF, and pleckstrin domain protein 1 (FARP1) expression is related to poor prognosis. Analyses in 91 clinical advanced gastric cancers of the relationship of prognosis and pathological factors with immunohistochemical expression of FARP1 indicated that high expression of FARP1 is significantly associated with lymphatic invasion, lymph metastasis, and poor prognosis of the patients (P = 0.025). In gastric cancer cells, FARP1 knockdown decreased cell motility, whereas FARP1 overexpression promoted cell motility and filopodium formation via CDC42 activation. FARP1 interacted with integrin beta 5, and a potent integrin alpha v beta 5 inhibitor (SB273005) prevented cell motility in only high FARP1-expressing gastric cancer cells. These results suggest that the integrin alpha v beta 5-FARP1-CDC42 axis plays a crucial role in gastric cancer cell migration and invasion. Thus, regulatory cascade upstream of Rho can be a specific and promising target of advanced cancer treatment.