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Topics {✒️}

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         headline:Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness
         description: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. 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. 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. 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.
         datePublished:2020-01-11T00:00:00Z
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      headline:Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness
      description: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. 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. 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. 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.
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         MYPT1 (PPP1R12A)
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         Stemness
         Cancer Research
         Oncology
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            address:
               name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
               type:PostalAddress
            type:Organization
            name:CIBERONC, Instituto de Salud Carlos III
            address:
               name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Marco Perez
      affiliation:
            name:Universidad de Sevilla, Consejo Superior de Investigaciones Científicas
            address:
               name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
               type:PostalAddress
            type:Organization
            name:CIBERONC, Instituto de Salud Carlos III
            address:
               name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Manuel P. Jiménez-García
      affiliation:
            name:Universidad de Sevilla, Consejo Superior de Investigaciones Científicas
            address:
               name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
               type:PostalAddress
            type:Organization
            name:CIBERONC, Instituto de Salud Carlos III
            address:
               name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Elisa Suarez-Martinez
      affiliation:
            name:Universidad de Sevilla, Consejo Superior de Investigaciones Científicas
            address:
               name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
               type:PostalAddress
            type:Organization
            name:CIBERONC, Instituto de Salud Carlos III
            address:
               name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Purificacion Estevez-Garcia
      affiliation:
            name:Universidad de Sevilla, Consejo Superior de Investigaciones Científicas
            address:
               name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
               type:PostalAddress
            type:Organization
            name:CIBERONC, Instituto de Salud Carlos III
            address:
               name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Amancio Carnero
      url:http://orcid.org/0000-0003-4357-3979
      affiliation:
            name:Universidad de Sevilla, Consejo Superior de Investigaciones Científicas
            address:
               name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
               type:PostalAddress
            type:Organization
            name:CIBERONC, Instituto de Salud Carlos III
            address:
               name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
      name:Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
      name:CIBERONC, Instituto de Salud Carlos III, Madrid, Spain

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