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J Exp Clin Cancer Res. 2017 Oct 26;36(1):150. doi: 10.1186/s13046-017-0617-y.

Musashi-2, a novel oncoprotein promoting cervical cancer cell growth and invasion, is negatively regulated by p53-induced miR-143 and miR-107 activation.

Author information

1
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, 0608638, Japan. dpx1cn@gmail.com.
2
Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. tdken999@163.com.
3
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, 0608638, Japan.
4
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. jyue@uthsc.edu.
5
Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. jyue@uthsc.edu.
6
Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, 0608638, Japan.

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.

KEYWORDS:

Anti-tumor antibiotic; C-FOS; Cervical cancer; Metastasis; Mithramycin a; Musashi-2; microRNA-107; microRNA-143; p53

PMID:
29073938
PMCID:
PMC5659032
DOI:
10.1186/s13046-017-0617-y
[Indexed for MEDLINE]
Free PMC Article

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