Tumor suppressor FHIT regulates tumor invasion of pancreatic cancer cells via inhibiting association of Ezrin and Actin cytoskeleton

肿瘤抑制因子 FHIT 通过抑制 Ezrin 和肌动蛋白细胞骨架的结合来调节胰腺癌细胞的肿瘤侵袭

• 批准号: 23592009
• 负责人: NISHIZAKI Masahiko
• 金额: $ 3.24万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23592009/
• 关键词: 遺伝子治療; 癌; 転移・浸潤; FHIT; PKC; 膵癌

Ezrin is recognized as a key component in tumor metastasis and regulated by PKC. Abnormalities of tumor suppressor FHIT, whitch shares homology with PKCI (PKC-interacting protein), have been found in pancreatic cancers. In this study, we showed that FHIT overexpression in S2-VP10 pancreatic adenocarcinoma cells by transfection of Ad- FHIT suppressed migratory/invasive capacities of tumor cells. We observed that overexpression of FHIT largely reduced threonine-phosphorylated Ezrin. Furthermore, FHIT overexpression interrupted not only Ezrin and Actin cytoskeleton interaction but also Ezrin and PKC alpha interaction. We also found Fhit and PKC alpha binding in the immunoprecipitation analysis. Ectopic activation of FHIT significantly reduced the invasive potential in S2-VP10 cells. These findings suggested that overexpression of FHIT protein might regulate tumor invasion via inhibiting Ezrin and Actin cytoskeleton interaction.

Ezrin被认为是肿瘤转移的关键组分，并受PKC调节。FHIT基因与PKC-interacting protein（PKC-interacting protein，PKCI）具有同源性，在胰腺癌中有表达。在本研究中，我们发现通过转染Ad- FHIT在S2-VP 10胰腺癌细胞中过表达FHIT抑制肿瘤细胞的迁移/侵袭能力。 我们观察到FHIT的过度表达大大降低了苏氨酸磷酸化的Ezrin。 此外，FHIT过表达不仅中断Ezrin和肌动蛋白细胞骨架的相互作用，而且还中断Ezrin和PKC α的相互作用。 我们还发现Fhit和PKC α结合的免疫沉淀分析。FHIT的异位激活显著降低了S2-VP 10细胞的侵袭潜力。 这些结果表明FHIT蛋白的过表达可能通过抑制Ezrin和Actin细胞骨架的相互作用来调节肿瘤的侵袭。