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

Ezrin被认为是肿瘤转移的关键成分，并受PKC的调节。肿瘤抑制基因FHIT与PKCI(PKC相互作用蛋白)有同源性，已在胰腺癌中发现异常。在本研究中，我们通过腺病毒介导的FHIT在S2-VP10胰腺癌细胞中过表达，抑制了肿瘤细胞的迁移/侵袭能力。我们观察到，FHIT的过表达大大减少了苏氨酸磷酸化的Ezrin。此外，FHIT的过表达不仅中断了Ezrin和肌动蛋白细胞骨架的相互作用，而且还中断了Ezrin和PKCα的相互作用。免疫沉淀分析还发现FHIT和PKCα结合。FHIT的异位激活显著降低了S2-VP10细胞的侵袭力。这些结果提示，FHIT蛋白的过表达可能通过抑制Ezrin和肌动蛋白细胞骨架的相互作用来调节肿瘤的侵袭。

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.