Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Beijing, 100850, China.
Department of Stomatology, Chinese PLA General Hospital, Beijing, 100853, China.
Sci Rep. 2017 Aug 2;7(1):7153. doi: 10.1038/s41598-017-07332-3.
GADD45A (growth arrest and DNA damage inducible alpha), a stress response gene induced by genotoxic and nongenotoxic stresses, is implicated in various key processes, including the control of cell cycle checkpoints and DNA repair. The expression of GADD45A is directly regulated by numerous transcription factors, with p53 being the most representative. Moreover, post-transcriptional regulation also plays a role in GADD45A expression. However, little is known about the regulatory effects of microRNAs (miRNAs) on GADD45A expression. As a potential tumour suppressor, miR-138 has pleiotropic biological functions in various cancers. We have previously reported p53-mediated activation of miR-138 in human non-small-cell lung cancer (NSCLC) cells. In this study, we found that miR-138 specifically targeted AGO2, which affects the stability and maturation of miR-130b. Decreased expression of miR-130b promoted the expression of GADD45A and resulted in the G2/M phase arrest and proliferation inhibition in human NSCLC cells. Our results suggested that p53 could alternatively upregulate GADD45A in human NSCLC cells through a post-transcriptional pathway in which miR-138 is involved.
GADD45A（生长停滞和 DNA 损伤诱导的α）是一种应激反应基因，可被遗传毒性和非遗传毒性应激诱导，它参与了多种关键过程，包括细胞周期检查点和 DNA 修复的控制。GADD45A 的表达受许多转录因子的直接调控，其中 p53 是最具代表性的转录因子。此外，转录后调控也在 GADD45A 的表达中发挥作用。然而，关于 microRNAs（miRNAs）对 GADD45A 表达的调控作用知之甚少。miR-138 作为一种潜在的肿瘤抑制因子，在多种癌症中具有多种生物学功能。我们之前曾报道过 p53 在人非小细胞肺癌（NSCLC）细胞中对 miR-138 的介导激活。在本研究中，我们发现 miR-138 特异性靶向 AGO2，影响 miR-130b 的稳定性和成熟。miR-130b 的表达降低促进了 GADD45A 的表达，导致人非小细胞肺癌细胞停滞在 G2/M 期并抑制增殖。我们的结果表明，p53 可以通过一种涉及 miR-138 的转录后途径，在人非小细胞肺癌细胞中替代性地上调 GADD45A。
