RT Journal Article T1 Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness A1 Muñoz-Galván, Sandra A1 Felipe-Abrio, Blanca A1 Verdugo-Sivianes, Eva M. A1 Perez, Marco A1 Jiménez-García, Manuel P. A1 Suarez-Martinez, Elisa A1 Estevez-Garcia, Purificacion A1 Carnero, Amancio K1 Ovarian cancer K1 MYPT1 (PPP1R12A) K1 MiR-30b K1 Therapy resistance K1 Hippo pathway K1 Stemness K1 Cisplatin K1 Chemotherapy K1 Neoplasias ováricas K1 Vía de señalización hippo K1 Cisplatino K1 Quimioterapia AB Background: Ovarian cancer is one of the most common and malignant cancers, partly due to its late diagnosis and high recurrence. Chemotherapy resistance has been linked to poor prognosis and is believed to be linked to the cancer stem cell (CSC) pool. Therefore, elucidating the molecular mechanisms mediating therapy resistance is essential to finding new targets for therapy-resistant tumors. Methods: shRNA depletion of MYPT1 in ovarian cancer cell lines, miRNA overexpression, RT-qPCR analysis, patient tumor samples, cell line- and tumorsphere-derived xenografts, in vitro and in vivo treatments, analysis of data from ovarian tumors in public transcriptomic patient databases and in-house patient cohorts. Results: We show that MYPT1 (PPP1R12A), encoding myosin phosphatase target subunit 1, is downregulated in ovarian tumors, leading to reduced survival and increased tumorigenesis, as well as resistance to platinum-based therapy. Similarly, overexpression of miR-30b targeting MYPT1 results in enhanced CSC-like properties in ovarian tumor cells and is connected to the activation of the Hippo pathway. Inhibition of the Hippo pathway transcriptional co-activator YAP suppresses the resistance to platinum-based therapy induced by either low MYPT1 expression or miR-30b overexpression, both in vitro and in vivo. Conclusions: Our work provides a functional link between the resistance to chemotherapy in ovarian tumors and the increase in the CSC pool that results from the activation of the Hippo pathway target genes upon MYPT1 downregulation. Combination therapy with cisplatin and YAP inhibitors suppresses MYPT1-induced resistance, demonstrating the possibility of using this treatment in patients with low MYPT1 expression, who are likely to be resistant to platinum-based therapy. PB BioMed Central, Springer Nature YR 2020 FD 2020-01-11 LK http://hdl.handle.net/10668/4330 UL http://hdl.handle.net/10668/4330 LA en NO Muñoz-Galván S, Felipe-Abrio B, Verdugo-Sivianes EM, Perez M, Jiménez-García MP, Suarez-Martinez E, et al. Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness. Mol Cancer. 2020 Jan 11;19(1):7 DS RISalud RD Apr 18, 2025