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 language | English |
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Article number | 150 |
Number of pages | 12 |
Journal | J Exp Clin Cancer Res |
Volume | 36 |
Issue number | 1 |
Early online date | 26 Oct 2017 |
DOIs | |
Publication status | Published - 26 Oct 2017 |
Bibliographical note
Acknowledgement: We thank Dr. Zhujie Xu for technical assistance.Funding: This work was supported by a grant from the Department of Women’s
Health Educational System, JSPS Grant-in-Aid for Scientific Research (C)
(15 K10697 and 16 K11123) and the Science and Technology Planning
Project of Guangdong Province, China (2014A0202121
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