title: Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop.
abstract: 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.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Ge
authors.forename: Z-G
authors.initials: ZG
authors.lastname: Han
authors.forename: W-T
authors.initials: WT
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2