miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response

Abstract

Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.

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Figure 1: Expression of the miR-200s is stimulated by oxidative stress.
Figure 2: Balance of the p38 and JNK pathways by miR-141 and miR-200a.
Figure 3: miR-141 and miR-200a enhance tumorigenesis in mouse models.
Figure 4: miR-200a and oxidative stress response predict good prognosis in patients with ovarian cancer.
Figure 5: miR-141 and miR-200a enhance the response to chemotherapeutic reagents.

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Acknowledgements

We thank O. Delattre and S. Chanock for fruitful discussions and comments on the manuscript. We acknowledge S. Alran and B. Baranger (Surgery Department of Institut Curie) and the Biological Resource Center of Institut Curie for providing human ovarian tumors and B. Hasselain and D. Hajage for advice regarding our statistical analyses. We thank the members of the animal facility and the flow-cytometry platform of Institut Curie for their expertise. The experimental work was supported by grants from Institut National de la Santé et de la Recherche Médicale, the Institut Curie, the Ligue Nationale Contre le Cancer, the Institut National du Cancer and the Association pour la Recherche Contre le Cancer. B.M. was supported by a post-doctoral fellowship from the INSERM Avenir program and the Association pour la Recherche Contre le Cancer.

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B.M. and F.M.-G. participated in the conception and design of the experiments. B.M., L.B., M.C., T.G. and Y.d.F. performed the experiments. X.S.-G. selected the human ovarian cancers after adapted characterization, and J.-P.M. provided transcriptome data. P.C. provided the associated clinical data from the subjects. O.M. and A.N. provided technical assistance and expertise in the ovarian tumor sample preparation. J.-P.M., B.M., L.B. and M.C. contributed to the statistical analyses of the data. F.M.-G. wrote the paper with suggestions and comments from all authors.

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Correspondence to Fatima Mechta-Grigoriou.

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Mateescu, B., Batista, L., Cardon, M. et al. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med 17, 1627–1635 (2011). https://doi.org/10.1038/nm.2512

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