Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Proliferation
Cisplatin
/ pharmacology
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Hippo Signaling Pathway
Humans
Mice
Mice, Nude
MicroRNAs
/ genetics
Neoplasm Invasiveness
Neoplasm Recurrence, Local
/ drug therapy
Neoplastic Stem Cells
/ drug effects
Ovarian Neoplasms
/ drug therapy
Prognosis
Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Hippo pathway
MYPT1 (PPP1R12A)
Ovarian cancer
Stemness
Therapy resistance
miR-30b
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
11 01 2020
11 01 2020
Historique:
received:
14
09
2019
accepted:
01
01
2020
entrez:
14
1
2020
pubmed:
14
1
2020
medline:
13
1
2021
Statut:
epublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 31926547
doi: 10.1186/s12943-020-1130-z
pii: 10.1186/s12943-020-1130-z
pmc: PMC6954568
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
MIRN30b microRNA, human
0
MicroRNAs
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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