期刊
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
卷 36, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13046-017-0617-y
关键词
Musashi-2; C-FOS; p53; microRNA-143; microRNA-107; Mithramycin a; Anti-tumor antibiotic; Cervical cancer; Metastasis
类别
资金
- Department of Women's Health Educational System
- JSPS [15 K10697, 16 K11123]
- Science and Technology Planning Project of Guangdong Province, China [2014A020212124]
- Grants-in-Aid for Scientific Research [16K11123, 15K10697] Funding Source: KAKEN
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.
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