Muñoz-Galván, SandraFelipe-Abrio, BlancaVerdugo-Sivianes, Eva M.Perez, MarcoJiménez-García, Manuel P.Suarez-Martinez, ElisaEstevez-Garcia, PurificacionCarnero, Amancio2022-11-072022-11-072020-01-11Muñoz-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):7http://hdl.handle.net/10668/4330Background: 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Ovarian cancerMYPT1 (PPP1R12A)MiR-30bTherapy resistanceHippo pathwayStemnessCisplatinChemotherapyNeoplasias ováricasVía de señalización hippoCisplatinoQuimioterapiaMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic AgentsMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::ApoptosisMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Growth::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Platinum Compounds::CisplatinMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, NeoplasticMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, NudeMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAsMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm InvasivenessMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm Recurrence, LocalMedical Subject Headings::Anatomy::Cells::Stem Cells::Neoplastic Stem CellsMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian NeoplasmsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::PrognosisMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine KinasesMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal TransductionMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Mortality::Survival RateMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Tumor Cells, CulturedMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Evaluation Studies as Topic::Drug Evaluation, Preclinical::Drug Screening Assays, Antitumor::Xenograft Model Antitumor AssaysMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasmresearch article31926547open access10.1186/s12943-020-1130-z1476-4598PMC6954568