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Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia

The development of drug resistance remains one of the major challenges to current chemotherapeutic regimens in gestational trophoblastic neoplasia (GTN). Further understanding on the mechanisms of drug resistance would help to develop more effective therapy to treat GTN. Herein, tandem mass tag-base...

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Autores principales: Jun, Fu, Peng, Zheng, Zhang, Yi, Shi, Dazun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198745/
https://www.ncbi.nlm.nih.gov/pubmed/32411596
http://dx.doi.org/10.3389/fonc.2020.00557
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author Jun, Fu
Peng, Zheng
Zhang, Yi
Shi, Dazun
author_facet Jun, Fu
Peng, Zheng
Zhang, Yi
Shi, Dazun
author_sort Jun, Fu
collection PubMed
description The development of drug resistance remains one of the major challenges to current chemotherapeutic regimens in gestational trophoblastic neoplasia (GTN). Further understanding on the mechanisms of drug resistance would help to develop more effective therapy to treat GTN. Herein, tandem mass tag-based (TMT) quantitative proteomic technique was used to establish drug resistance-related proteomic profiles in chemoresistant GTN cell models (JEG3/MTX, JEG3/VP16, JEG3/5-Fu). In total, we identified 5,704 protein groups, among which 4,997 proteins were quantified in JEG3 and its chemoresistant sublines. Bioinformatics analysis revealed that multiple biological processes/molecular pathways/signaling networks were involved in the regulation of drug resistance in chemoresistant JEG3 sublines. SOX8 was upregulated in all the three chemoresistant sublines, and its function was further investigated. Knockdown of SOX8 significantly reduced cell viability, impaired soft agar clonogenesis, and increased caspase-3 activities after drug treatment in JEG3 chemoresistant sublines. In addition, over-expression of SOX8 promoted cell survival, enhanced soft agar clonogenesis, and attenuated caspase-3 activities after drug treatment in GTN cells. Importantly, SOX8 might be a potential regulator of reactive oxygen species (ROS) homeostasis, as SOX8 regulated the expression of antioxidant enzymes (GPX1, HMOX1) and reduced drug-induced ROS accumulation in GTN cell models. Collectively, SOX8 might promote drug resistance through attenuating the accumulation of ROS induced by chemotherapeutic drugs in GTN cells. Targeting SOX8 might be useful to sensitize GTN cells to chemotherapy.
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spelling pubmed-71987452020-05-14 Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia Jun, Fu Peng, Zheng Zhang, Yi Shi, Dazun Front Oncol Oncology The development of drug resistance remains one of the major challenges to current chemotherapeutic regimens in gestational trophoblastic neoplasia (GTN). Further understanding on the mechanisms of drug resistance would help to develop more effective therapy to treat GTN. Herein, tandem mass tag-based (TMT) quantitative proteomic technique was used to establish drug resistance-related proteomic profiles in chemoresistant GTN cell models (JEG3/MTX, JEG3/VP16, JEG3/5-Fu). In total, we identified 5,704 protein groups, among which 4,997 proteins were quantified in JEG3 and its chemoresistant sublines. Bioinformatics analysis revealed that multiple biological processes/molecular pathways/signaling networks were involved in the regulation of drug resistance in chemoresistant JEG3 sublines. SOX8 was upregulated in all the three chemoresistant sublines, and its function was further investigated. Knockdown of SOX8 significantly reduced cell viability, impaired soft agar clonogenesis, and increased caspase-3 activities after drug treatment in JEG3 chemoresistant sublines. In addition, over-expression of SOX8 promoted cell survival, enhanced soft agar clonogenesis, and attenuated caspase-3 activities after drug treatment in GTN cells. Importantly, SOX8 might be a potential regulator of reactive oxygen species (ROS) homeostasis, as SOX8 regulated the expression of antioxidant enzymes (GPX1, HMOX1) and reduced drug-induced ROS accumulation in GTN cell models. Collectively, SOX8 might promote drug resistance through attenuating the accumulation of ROS induced by chemotherapeutic drugs in GTN cells. Targeting SOX8 might be useful to sensitize GTN cells to chemotherapy. Frontiers Media S.A. 2020-04-28 /pmc/articles/PMC7198745/ /pubmed/32411596 http://dx.doi.org/10.3389/fonc.2020.00557 Text en Copyright © 2020 Jun, Peng, Zhang and Shi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Jun, Fu
Peng, Zheng
Zhang, Yi
Shi, Dazun
Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia
title Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia
title_full Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia
title_fullStr Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia
title_full_unstemmed Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia
title_short Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia
title_sort quantitative proteomic profiling identifies sox8 as novel regulator of drug resistance in gestational trophoblastic neoplasia
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198745/
https://www.ncbi.nlm.nih.gov/pubmed/32411596
http://dx.doi.org/10.3389/fonc.2020.00557
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