Department of Biological Sciences, University of Lethbridge , Lethbridge , Canada.
Department of Agronomy, College of Agriculture, Yangzhou University , Yangzhou , P.R. China.
Cell Cycle. 2019 Nov;18(21):2876-2892. doi: 10.1080/15384101.2019.1652033. Epub 2019 Sep 16.
Glioblastoma is the most aggressive brain tumor. Although miR-141 has been demonstrated to primarily function as a tumor suppressor in numerous malignancies, including glioblastoma, the mechanisms involved remain poorly understood. Here, it is shown that miR-141 is downregulated in glioblastoma cell lines and tissues and may exert its biological function via directly targeting (). Using two glioblastoma cell lines that differ from each other by the functionality of DNA-dependent protein kinase (DNAPK), a functional involvement of DNAPK in the miR-141 tumor suppression network was observed. In M059K cells with a normal function of DNAPK, the enforced expression of miR-141 attenuated MYT1L expression and suppressed cell proliferation. Conversely, the inhibition of miR-141 expression promoted cell proliferation; however, in M059J cells with a loss-of-function DNAPK, miR-141 constitutively inhibited cell proliferation upon ectopic overexpression or inhibition. An overexpression of miR-141 suppressed M059J cell migration, while it had no effect on M059K. Furthermore, the ectopic expression of miR-141 induced an S-phase arrest in both cell lines, whereas the inhibition of miR-141 caused a G1 arrest in M059J and accelerated the S phase in M059K. An overexpression and suppression of miR-141 resulted in an aberrant expression of cell-cycle proteins, including p21. Moreover, MYT1L may be a transcription factor of p21 in p53-mutant cells, whereas DNAPK may function as a repressor of MYT1L. The findings revealed the crucial role of DNAPK in miR-141-mediated suppression of gliomagenesis and demonstrated that it may be a target molecule in miR-141-associated therapeutic interventions for glioblastoma.
胶质母细胞瘤是最具侵袭性的脑肿瘤。虽然 miR-141 已被证明在许多恶性肿瘤中主要作为肿瘤抑制因子发挥作用，包括胶质母细胞瘤，但相关机制仍知之甚少。在这里，研究表明 miR-141 在胶质母细胞瘤细胞系和组织中下调，可能通过直接靶向 () 发挥其生物学功能。使用两种胶质母细胞瘤细胞系，它们在 DNA 依赖性蛋白激酶 (DNAPK) 的功能上存在差异，观察到 DNAPK 在 miR-141 肿瘤抑制网络中的功能参与。在 DNAPK 功能正常的 M059K 细胞中，强制表达 miR-141 减弱了 MYT1L 的表达并抑制了细胞增殖。相反，抑制 miR-141 的表达促进了细胞增殖；然而，在具有失活的 DNAPK 的 M059J 细胞中，miR-141 在外源过表达或抑制时持续抑制细胞增殖。miR-141 的过表达抑制了 M059J 细胞的迁移，而对 M059K 则没有影响。此外，miR-141 的异位表达在两种细胞系中均诱导 S 期停滞，而 miR-141 的抑制导致 M059J 的 G1 期停滞并加速 M059K 的 S 期。miR-141 的过表达和抑制导致细胞周期蛋白的异常表达，包括 p21。此外，在 p53 突变细胞中，MYT1L 可能是 p21 的转录因子，而 DNAPK 可能作为 MYT1L 的抑制剂发挥作用。研究结果揭示了 DNAPK 在 miR-141 介导的抑制胶质母细胞瘤发生中的关键作用，并表明它可能是 miR-141 相关治疗胶质母细胞瘤干预的靶分子。
