FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer.,Oncogenesis

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FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer.
Oncogenesis ( IF 5.9 ) Pub Date : 2020-02-06 , DOI: 10.1038/s41389-020-0190-7
Takuro Hirano _{1,

2} , Yoshinari Shinsato ₂ , Kan Tanabe ₁ , Nayuta Higa _{2,

3} , Muhammad Kamil _{2,

3} , Kohichi Kawahara ₂ , Masatatsu Yamamoto ₂ , Kentaro Minami ₂ , Michiko Shimokawa ₂ , Takaaki Arigami _{1,

4} , Shigehiro Yanagita ₁ , Daisuke Matushita ₁ , Yoshikazu Uenosono ₁ , Sumiya Ishigami ₁ , Yuko Kijima ₁ , Kosei Maemura ₁ , Ikumi Kitazono ₅ , Akihide Tanimoto _{5,

6} , Tatsuhiko Furukawa _{2,

6} , Shoji Natsugoe _{1,

4,

6}

Affiliation

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 β5, and a potent integrin αvβ5 inhibitor (SB273005) prevented cell motility in only high FARP1-expressing gastric cancer cells. These results suggest that the integrin αvβ5-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.

中文翻译：

FARP1增强整合素αvβ5信号传导的CDC42活性，并与晚期胃癌的不良预后相关。

考虑到大多数晚期癌症的不良预后，预防侵袭和转移对于疾病控制至关重要。Ras同源（Rho）鸟嘌呤交换因子（GEF）及其信号级联反应可能是晚期癌症的潜在治疗靶标。我们对癌症基因组图谱的表达数据进行了计算机分析，以鉴定在晚期胃癌中显示异常表达的候选Rho-GEF基因，并发现FERM，Rho / ArhGEF和pleckstrin域蛋白1（FARP1）的表达与预后不良有关。分析了91例临床晚期胃癌的预后和病理因素与FARP1免疫组织化学表达的关系，表明FARP1的高表达与患者的淋巴管浸润，淋巴转移和不良预后显着相关（P = 0.025）。在胃癌细胞中，FARP1敲低会降低细胞运动性，而FARP1的过表达则通过CDC42激活促进细胞运动性和fi的形成。FARP1与整合素β5相互作用，有效的整合素αvβ5抑制剂（SB273005）仅在高FARP1表达的胃癌细胞中阻止细胞运动。这些结果表明，整联蛋白αvβ5-FARP1-CDC42轴在胃癌细胞的迁移和侵袭中起着至关重要的作用。因此，Rho上游的调控级联反应可以成为晚期癌症治疗的特定且有希望的靶标。有效的整联蛋白αvβ5抑制剂（SB273005）仅在高FARP1表达的胃癌细胞中阻止细胞运动。这些结果表明，整联蛋白αvβ5-FARP1-CDC42轴在胃癌细胞的迁移和侵袭中起着至关重要的作用。因此，Rho上游的调控级联反应可以成为晚期癌症治疗的特定且有希望的靶标。有效的整联蛋白αvβ5抑制剂（SB273005）仅在高FARP1表达的胃癌细胞中阻止细胞运动。这些结果表明，整联蛋白αvβ5-FARP1-CDC42轴在胃癌细胞的迁移和侵袭中起着至关重要的作用。因此，Rho上游的调控级联反应可以成为晚期癌症治疗的特定且有希望的靶标。

更新日期：2020-02-06

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