Details

Autor(en) / Beteiligte

• Vernon, Mégane
• Lambert, Bernard
• Meryet-Figuière, Matthieu
• Brotin, Emilie
• Weiswald, Louis-Bastien
• Paysant, Hippolyte
• Vigneron, Nicolas
• Wambecke, Anaïs
• Abeilard, Edwige
• Giffard, Florence
• Louis, Marie-Helene
• Blanc-Fournier, Cécile
• Gauduchon, Pascal
• Poulain, Laurent
• Denoyelle, Christophe

Titel

Functional miRNA screening identifies wide-ranging antitumor properties of miR-3622b-5p and reveals a new therapeutic combination strategy in ovarian tumor organoids

Ist Teil von

• Molecular cancer therapeutics, 2020-07, Vol.19 (7), p.1506-1519

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Novel therapeutic strategies are urgently required for the clinical management of chemoresistant ovarian carcinoma, which is the most lethal of the gynecological malignancies. MicroRNAs (miRNAs) hold promise because they play a critical role in determining the cell phenotype by regulating several hundreds of targets, which could constitute vulnerabilities of cancer cells. A combination of gain of function miRNA screening and real-time continuous cell monitoring allows the identification of miRNAs with robust cytotoxic effects in chemoresistant ovarian cancer cells. Focusing on miR-3622b-5p, we show that it induces apoptosis in several ovarian cancer cell lines by both directly targeting Bcl-xL and EGFR mediating BIM upregulation. MiR-3622b-5p also sensitizes cells to cisplatin by inhibiting Bcl-xL in ovarian cancer cell lines escaping BIM induction. MiR-3622b-5p also exerts anti migratory capacities by targeting both LIMK1 and NOTCH1. These wide ranging antitumor properties of miR-3622b-5p in ovarian cancer cells are mimicked by the associations of pharmacological inhibitors targeting these proteins. The combination of an EGFR inhibitor together with a BH3-mimetic molecule induced a large decrease in cell viability in a panel of ovarian cancer cell lines and several ovarian patient derived tumor organoids, suggesting the value of pursuing such a combination therapy in ovarian carcinoma. Altogether, our work highlights the potential of phenotype based miRNA screening approaches to identify lethal interactions which might lead to new drug combinations and clinically applicable strategies.