Musashi-2, a novel oncoprotein promoting cervical cancer cell growth and invasion, is negatively regulated by p53-induced miR-143 and miR-107 activation. Journal of experimental & clinical cancer research : CR

Peixin Dong, Ying Xiong, Sharon J. B. Hanley, Junming Yue, Hidemichi Watari

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Although previous studies have shown promise for targeting Musashi RNA-binding protein 2 (MSI-2) in diverse tumors, the role and mechanism of MSI-2 for cervical cancer (CC) progression and the regulation of MSI-2 expression remains unclear. METHODS: Using gene expression and bioinformatic analysis, together with gain- and loss-of-function assays, we identified MSI-2 as a novel oncogenic driver and a poor prognostic marker in CC. We explored the regulation of c-FOS by MSI-2 via RNA-immunoprecipitation and luciferase assay, and confirmed a direct inhibition of MSI-2 by miR-143/miR-107 using luciferase assay. We assessed the effect of a natural antibiotic Mithramycin A on p53, miR-143/miR-107 and MSI-2 expression in CC cells. RESULTS: MSI-2 mRNA is highly expressed in CC tissues and its overexpression correlates with lower overall survival. MSI-2 promotes CC cell growth, invasiveness and sphere formation through directly binding to c-FOS mRNA and by increasing c-FOS protein expression. Furthermore, miR-143/miR-107 are two tumor suppressor miRNAs that directly bind and inhibit MSI-2 expression in CC cells, and downregulation of miR-143/miR-107 associates with poor patient prognosis. Importantly, we found that p53 decreases the expression of MSI-2 through elevating miR-143/miR-107 levels, and treatment with a natural antibiotic Mithramycin A increased p53 and miR-143/miR-107 expression and reduced MSI-2 expression, resulting in the inhibition of CC cell proliferation, invasion and sphere formation. CONCLUSIONS: These results suggest that MSI-2 plays a crucial role in promoting the aggressive phenotypes of CC cells, and restoration of miR-143/miR-107 by Mithramycin A via activation of p53 may represent a novel therapeutic approach for CC.
Original languageEnglish
Article number150
Number of pages12
JournalJ Exp Clin Cancer Res
Volume36
Issue number1
DOIs
Publication statusPublished - 26 Oct 2017

Keywords

  • Female
  • Humans
  • Cell Line, Tumor
  • Disease Progression
  • Cervical cancer
  • Neoplasm Invasiveness
  • Gene Expression Regulation, Neoplastic
  • MicroRNAs/*genetics
  • *Up-Regulation
  • Anti-tumor antibiotic
  • C-FOS
  • Cell Movement
  • Cell Proliferation
  • HeLa Cells
  • Metastasis
  • microRNA-107
  • microRNA-143
  • Mithramycin a
  • Musashi-2
  • p53
  • Prognosis
  • Proto-Oncogene Proteins c-fos/*genetics/metabolism
  • RNA-Binding Proteins/*genetics/metabolism
  • Tumor Suppressor Protein p53/*genetics/metabolism
  • Uterine Cervical Neoplasms/*genetics/metabolism

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