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Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway

BACKGROUND: Cancer cell viability is strongly modulated by the Hippo pathway, which includes mammalian STE20-like protein kinase 1 (Mst1) and yes-associated protein (Yap). Although the roles of Mst1 and Yap in thyroid carcinoma cell death have been fully addressed, no study has determined whether di...

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Autores principales: Zhang, Xiaoli, Li, Fei, Cui, Yeqing, Liu, Shuang, Sun, Haichen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530088/
https://www.ncbi.nlm.nih.gov/pubmed/31139020
http://dx.doi.org/10.1186/s12935-019-0860-8
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author Zhang, Xiaoli
Li, Fei
Cui, Yeqing
Liu, Shuang
Sun, Haichen
author_facet Zhang, Xiaoli
Li, Fei
Cui, Yeqing
Liu, Shuang
Sun, Haichen
author_sort Zhang, Xiaoli
collection PubMed
description BACKGROUND: Cancer cell viability is strongly modulated by the Hippo pathway, which includes mammalian STE20-like protein kinase 1 (Mst1) and yes-associated protein (Yap). Although the roles of Mst1 and Yap in thyroid carcinoma cell death have been fully addressed, no study has determined whether differential modification of Mst1 and Yap could further suppress thyroid carcinoma progression. The aim of our study was to explore the antiapoptotic effects exerted by combined Mst1 overexpression and Yap knockdown in thyroid carcinoma MDA-T32 cells in vitro. METHODS: Mst1 adenovirus and Yap shRNA were transfected into MDA-T32 cells to overexpress Mst1 and inhibit Yap, respectively. Cell viability and death were determined via an MTT assay, a TUNEL assay and western blotting. Mitochondrial function, mitochondrial fission and pathway studies were performed via western blotting and immunofluorescence. RESULTS: The results of our study showed that combined Mst1 overexpression and Yap knockdown further augmented MDA-T32 cell death by mediating mitochondrial damage. In addition, cancer cell migration and proliferation were suppressed by combined Mst1 overexpression and Yap knockdown. At the molecular level, mitochondrial membrane potential, ATP production, respiratory function, and caspase-9-related apoptosis were activated by combined Mst1 overexpression and Yap knockdown. Further, we found that fatal mitochondrial fission was augmented by combined Mst1 overexpression and Yap knockdown in a manner dependent on the JNK-MIEF1 pathway. Inhibition of JNK-MIEF1 pathway activity abolished the proapoptotic effects exerted by Mst1/Yap on MDA-T32 cells. CONCLUSIONS: Taken together, our data suggest that Mst1 activation and Yap inhibition coordinate to augment thyroid cancer cell death by controlling the JNK-MIEF1-mitochondria pathway, suggesting that differential regulation of the core Hippo pathway components is potentially a novel therapeutic tool for the treatment of thyroid cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-019-0860-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-65300882019-05-28 Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway Zhang, Xiaoli Li, Fei Cui, Yeqing Liu, Shuang Sun, Haichen Cancer Cell Int Primary Research BACKGROUND: Cancer cell viability is strongly modulated by the Hippo pathway, which includes mammalian STE20-like protein kinase 1 (Mst1) and yes-associated protein (Yap). Although the roles of Mst1 and Yap in thyroid carcinoma cell death have been fully addressed, no study has determined whether differential modification of Mst1 and Yap could further suppress thyroid carcinoma progression. The aim of our study was to explore the antiapoptotic effects exerted by combined Mst1 overexpression and Yap knockdown in thyroid carcinoma MDA-T32 cells in vitro. METHODS: Mst1 adenovirus and Yap shRNA were transfected into MDA-T32 cells to overexpress Mst1 and inhibit Yap, respectively. Cell viability and death were determined via an MTT assay, a TUNEL assay and western blotting. Mitochondrial function, mitochondrial fission and pathway studies were performed via western blotting and immunofluorescence. RESULTS: The results of our study showed that combined Mst1 overexpression and Yap knockdown further augmented MDA-T32 cell death by mediating mitochondrial damage. In addition, cancer cell migration and proliferation were suppressed by combined Mst1 overexpression and Yap knockdown. At the molecular level, mitochondrial membrane potential, ATP production, respiratory function, and caspase-9-related apoptosis were activated by combined Mst1 overexpression and Yap knockdown. Further, we found that fatal mitochondrial fission was augmented by combined Mst1 overexpression and Yap knockdown in a manner dependent on the JNK-MIEF1 pathway. Inhibition of JNK-MIEF1 pathway activity abolished the proapoptotic effects exerted by Mst1/Yap on MDA-T32 cells. CONCLUSIONS: Taken together, our data suggest that Mst1 activation and Yap inhibition coordinate to augment thyroid cancer cell death by controlling the JNK-MIEF1-mitochondria pathway, suggesting that differential regulation of the core Hippo pathway components is potentially a novel therapeutic tool for the treatment of thyroid cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-019-0860-8) contains supplementary material, which is available to authorized users. BioMed Central 2019-05-22 /pmc/articles/PMC6530088/ /pubmed/31139020 http://dx.doi.org/10.1186/s12935-019-0860-8 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Primary Research
Zhang, Xiaoli
Li, Fei
Cui, Yeqing
Liu, Shuang
Sun, Haichen
Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway
title Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway
title_full Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway
title_fullStr Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway
title_full_unstemmed Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway
title_short Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway
title_sort mst1 overexpression combined with yap knockdown augments thyroid carcinoma apoptosis via promoting mief1-related mitochondrial fission and activating the jnk pathway
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530088/
https://www.ncbi.nlm.nih.gov/pubmed/31139020
http://dx.doi.org/10.1186/s12935-019-0860-8
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