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

• Published in: Nature medicine Vol. 17; no. 12; pp. 1627 - 1635
• Main Authors: Mateescu, Bogdan, Batista, Luciana, Cardon, Melissa, Gruosso, Tina, de Feraudy, Yvan, Mariani, Odette, Nicolas, André, Meyniel, Jean-Philippe, Cottu, Paul, Sastre-Garau, Xavier, Mechta-Grigoriou, Fatima
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2011; Nature Publishing Group
• Subjects: 631/337/384/331; 692/420/755; 692/699/67/1517/1709; Adult; Aged; Aged, 80 and over; Animals; Antioxidants; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Down-Regulation; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Infectious Diseases; Metabolic Diseases; Mice; Mice, Nude; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Mitogen-Activated Protein Kinase 14 - genetics; Mitogen-Activated Protein Kinase 14 - metabolism; Molecular Medicine; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - pathology; Neurosciences; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Ovarian tumors; Oxidative Stress; Physiological aspects; Ribonucleic acid; RNA; Stress response; Tumors
• DOI: 10.1038/nm.2512
• ISSN: 1078-8956

This report identifies a new contribution of members of the miR-200 family to tumorigenesis. miR-200a and miR-141 specifically regulate p38α, contributing to the cellular modulation of oxidative stress responses. In this role, the miRs can accelerate ovarian tumorigenesis but also endow cancer cells with increased sensitivity to ROS-inducing chemotherapy. This two-part effect is reflected on the distinct association of the miRs with patient survival and may be informative for treatment decisions. 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.