Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huai-hai Road, Xuzhou, 221002, Jiangsu, PR China; Department of Neurosurgery, The First People's Hospital of Yancheng, The Forth Affiliated Hospital of Nantong University, Yancheng, 224006, Jiangsu, PR China.
Department of Neurosurgery, Suqian First Hospital, 120 Su Zhi Road, Suqian, 223800, Jiangsu, PR China.
Biochem Biophys Res Commun. 2019 Oct 1;517(4):588-595. doi: 10.1016/j.bbrc.2019.07.059. Epub 2019 Aug 5.
Fyn-related kinase (FRK), a member of the Src-related tyrosine kinase family, functions as a tumor suppressor in several malignancies. We previously showed that FRK overexpression inhibited the growth of glioma cells. However, it is unknown whether FRK is equally effective against intracranial glioma in vivo, and the mechanism by which FRK influences glioma cell growth remains unclear. In this study, we found that tumor volume was reduced by about one-third in mice with FRK overexpression, which showed improved survival relative to controls. Immunofluorescence analysis revealed that FRK overexpression inhibited glioma cell proliferation and induced their apoptosis. Importantly, in vitro we further found that FRK decreased the expression of integrin subunit β1 (ITGB1) at both the mRNA and protein levels. FRK also inhibited transactivation by ITGB1, resulting in the suppression of its target proteins AKT and focal adhesion kinase (FAK). ITGB1 overexpression promoted glioma cell growth and partially reduced FRK-induced growth suppression. These results indicate that FRK inhibits human glioma growth via regulating ITGB1/FAK signaling and provide a potential therapeutic target for the treatment of glioma.
Fyn 相关激酶（FRK）是Src 相关酪氨酸激酶家族的成员，在多种恶性肿瘤中作为肿瘤抑制因子发挥作用。我们之前的研究表明，FRK 过表达抑制了胶质瘤细胞的生长。然而，尚不清楚 FRK 在体内对颅内胶质瘤是否同样有效，以及 FRK 影响胶质瘤细胞生长的机制尚不清楚。在这项研究中，我们发现过表达 FRK 的小鼠肿瘤体积减少了约三分之一，与对照组相比，其存活率有所提高。免疫荧光分析显示，FRK 过表达抑制了胶质瘤细胞的增殖，并诱导其凋亡。重要的是，我们还在体外进一步发现 FRK 降低了整合素亚基β1（ITGB1）的 mRNA 和蛋白水平的表达。FRK 还抑制了 ITGB1 的反式激活，从而抑制了其靶蛋白 AKT 和黏着斑激酶（FAK）。ITGB1 的过表达促进了胶质瘤细胞的生长，并部分降低了 FRK 诱导的生长抑制。这些结果表明，FRK 通过调节 ITGB1/FAK 信号通路抑制人胶质母细胞瘤的生长，为胶质母细胞瘤的治疗提供了一个潜在的治疗靶点。
