Department of Anatomy, College of Medicine, Yeungnam University, 170 Hyeonchung-Ro, Nam-Gu, Daegu 42415, Korea.
Int J Mol Sci. 2019 Jul 19;20(14):3540. doi: 10.3390/ijms20143540.
MicroRNAs (miRNAs) can be used to target a variety of human malignancies by targeting their oncogenes or tumor suppressor genes. Recent evidence has shown that miRNA-1208 (miR-1208) was rarely expressed in a variety of cancer cells, suggesting the possibility that miR-1208 functions as a tumor suppressor gene. Herein, ectopic expression of miR-1208 induced the accumulation of sub-G1 populations and the cleavage of procaspase-3 and PARP, which could be prevented by pre-treatment with the pan-caspase inhibitor, Z-VAD. In addition, miR-1208 increased the susceptibility to cisplatin and TRAIL in Caki-1 cells. Luciferase reporter assay results showed that miR-1208 negatively regulates TBC1 domain containing kinase (TBCK) expression by binding to the miR-1208 binding sites in the 3'-untranslated region of TBCK. In addition, miR-1208 specifically repressed TBCK expression at the transcriptional level. In contrast, inhibition of endogenous miR-1208 by anti-miRs resulted in an increase in TBCK expression. Downregulation of TBCK induced by TBCK-specific siRNAs increased susceptibility to cisplatin and TRAIL. These findings suggest that miR-1208 acts as a tumor suppressor and targets TBCK directly, thus possessing great potential for use in renal cancer therapy.
微小 RNA（miRNA）可以通过靶向其癌基因或肿瘤抑制基因来靶向多种人类恶性肿瘤。最近的证据表明，miRNA-1208（miR-1208）在多种癌细胞中很少表达，这表明 miR-1208 可能作为肿瘤抑制基因发挥作用。在此，外源性表达 miR-1208 诱导亚 G1 群体的积累和 procaspase-3 和 PARP 的裂解，这可以通过用 pan-caspase 抑制剂 Z-VAD 预处理来预防。此外，miR-1208 增加了 Caki-1 细胞对顺铂和 TRAIL 的敏感性。荧光素酶报告基因检测结果表明，miR-1208 通过结合 TBCK 3'-UTR 中的 miR-1208 结合位点负调控 TBC1 结构域包含激酶（TBCK）的表达。此外，miR-1208 特异性地在转录水平上抑制 TBCK 的表达。相比之下，用 anti-miRs 抑制内源性 miR-1208 会导致 TBCK 表达增加。TBCK 特异性 siRNAs 下调诱导的 TBCK 表达增加了对顺铂和 TRAIL 的敏感性。这些发现表明 miR-1208 作为肿瘤抑制因子发挥作用，并直接靶向 TBCK，因此在肾癌治疗中具有很大的应用潜力。
