Department of Pathology and Laboratory Medicine, The Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Pathology and Laboratory Medicine, The Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
Cancer Lett. 2019 Nov 28;465:59-67. doi: 10.1016/j.canlet.2019.08.021. Epub 2019 Sep 3.
Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We found that miR-1 is expressed at relatively low levels in brain cancer patients, especially GBM. Ectopic miR-1 expression in GBM cells inhibited proliferation and migration, increased sensitivity to apoptosis induced by the DNA alkylating agent temozolomide in vitro, and inhibited GBM tumorigenesis in vivo. Expression of miR-1 in GBM cell lines directly targets fibronectin. High fibronectin expression in GBM correlates with poor patient survival and fibronectin expression is inversely correlated with miR-1 expression. Knockout of fibronectin expression in GBM cell lines inhibited proliferation and migration, increased sensitivity to apoptosis induced by temozolomide in vitro, and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring fibronectin levels in GBM cells ectopically expressing miR-1 increased tumorigenicity and decreased animal survival. Therefore, these results confirm that miR-1 has tumor suppressive activity in GBM by targeting fibronectin, and that the miR-1/fibronectin pathway may be a potential drug target in this devastating cancer.
胶质母细胞瘤（GBM）是一种致命且无法治愈的脑肿瘤。虽然 microRNAs（miRNAs）在调节癌细胞表型方面发挥着关键作用，但它们调节肿瘤发生的潜在机制尚不完全清楚。我们发现，miR-1 在脑癌患者，尤其是 GBM 患者中的表达水平相对较低。在 GBM 细胞中异位表达 miR-1 可抑制增殖和迁移，增加体外 DNA 烷化剂替莫唑胺诱导的细胞凋亡敏感性，并抑制体内 GBM 肿瘤发生。miR-1 在 GBM 细胞系中的表达直接靶向纤维连接蛋白。GBM 中高纤维连接蛋白表达与患者生存不良相关，纤维连接蛋白表达与 miR-1 表达呈负相关。在 GBM 细胞系中敲除纤维连接蛋白表达可抑制增殖和迁移，增加体外替莫唑胺诱导的细胞凋亡敏感性，并显著抑制 GBM 肿瘤生长和促进动物存活。相比之下，在异位表达 miR-1 的 GBM 细胞中恢复纤维连接蛋白水平可增加致瘤性并降低动物存活率。因此，这些结果证实 miR-1 通过靶向纤维连接蛋白在 GBM 中具有肿瘤抑制活性，miR-1/纤维连接蛋白途径可能是这种毁灭性癌症的潜在药物靶点。
