Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Oncogene. 2013 Jan 3;32(1):61-9. doi: 10.1038/onc.2012.28. Epub 2012 Feb 13.
Dysregulated microRNAs (miRNAs) have an important role in many malignant tumors. However, elucidating the roles of miRNAs in cancer biology, especially in epithelial cancers, remains an ongoing process. In this study, we show that both miR-143 and miR-145, which belong to the same miRNA cluster, can negatively modulate expression of their target gene, MDM2. The miR-143 and miR-145 is posttranscriptionally activated by upregulated p53, thereby generating a short miRNAs-MDM2-p53 feedback loop. Re-expression of these miRNAs suppresses cellular growth and triggers the apoptosis of epithelial cancer, in vitro and in vivo, by enhancing p53 activity via MDM2 turnover. Moreover, the miRNA-dependent MDM2 turnover contributes to the equilibrium of repeated p53 pulses in response to DNA damage stress. These findings suggest that MDM2 dysregulation caused by downregulation of miR-143 and miR-145 contributes to epithelial cancer development and has a key role in regulating cellular proliferation and apoptosis. Re-expression of miR-143 and miR-145 may be a reasonable strategy for treatment of epithelial cancers.
失调的 microRNAs（miRNAs）在许多恶性肿瘤中具有重要作用。然而，阐明 miRNAs 在癌症生物学中的作用，尤其是在上皮性癌症中的作用，仍然是一个持续的过程。在这项研究中，我们表明，属于同一 miRNA 簇的 miR-143 和 miR-145 可以负调控其靶基因 MDM2 的表达。miR-143 和 miR-145 通过上调的 p53 被转录后激活，从而产生一个短的 miRNAs-MDM2-p53 反馈环。这些 miRNAs 的重新表达通过 MDM2 周转增强 p53 活性，从而抑制上皮性癌细胞的体外和体内生长，并触发细胞凋亡。此外，miRNA 依赖性的 MDM2 周转有助于平衡对 DNA 损伤应激的重复 p53 脉冲。这些发现表明，miR-143 和 miR-145 的下调导致的 MDM2 失调有助于上皮性癌症的发展，并在调节细胞增殖和凋亡方面发挥关键作用。miR-143 和 miR-145 的重新表达可能是治疗上皮性癌症的合理策略。
