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ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma
Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133992/ https://www.ncbi.nlm.nih.gov/pubmed/27763636 http://dx.doi.org/10.1038/cddis.2016.328 |
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author | Li, Jun Ao, Jie Li, Kai Zhang, Jie Li, Yanyan Zhang, Le Wei, Yuyan Gong, Di Gao, Junping Tan, Weiwei Huang, Lugang Liu, Lunxu Lin, Ping Wei, Yuquan |
author_facet | Li, Jun Ao, Jie Li, Kai Zhang, Jie Li, Yanyan Zhang, Le Wei, Yuyan Gong, Di Gao, Junping Tan, Weiwei Huang, Lugang Liu, Lunxu Lin, Ping Wei, Yuquan |
author_sort | Li, Jun |
collection | PubMed |
description | Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells. In this study, we found that ZNF32 is upregulated by Sp1 (specificity protein 1) in response to drug treatment and that ZNF32 promotes drug resistance and protects AC cells against cisplatin or gefitinib treatment. ZNF32 overexpression in AC cells conferred resistance to EGFR (epidermal growth factor receptor) inhibitors by enhancing MEK/ERK activation. Moreover, ZNF32 was found to directly bind to the TGF-βR2 (transforming growth factor-beta receptor 2) promoter to promote its expression, and ZNF32-induced resistance was mediated by enhancing TGF-βR2 expression and activating the TGF-βR2/SMAD2 pathway. In both a mouse model and ex vivo cultured patient samples, a high level of ZNF32 expression was closely associated with worse overall survival and cisplatin resistance. ZNF32 appears to be a potential inducer of drug resistance that could increase the expression of the drug resistance-associated gene TGF-βR2 and subsequently facilitate the induction of drug resistance during both conventional chemotherapy and novel target therapy. Thus, ZNF32-associated target therapy is a potential novel adjuvant therapy that might effectively prevent the occurrence of multidrug resistance (MDR) during chemotherapy and improve the survival of patients with AC. |
format | Online Article Text |
id | pubmed-5133992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51339922016-12-16 ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma Li, Jun Ao, Jie Li, Kai Zhang, Jie Li, Yanyan Zhang, Le Wei, Yuyan Gong, Di Gao, Junping Tan, Weiwei Huang, Lugang Liu, Lunxu Lin, Ping Wei, Yuquan Cell Death Dis Original Article Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells. In this study, we found that ZNF32 is upregulated by Sp1 (specificity protein 1) in response to drug treatment and that ZNF32 promotes drug resistance and protects AC cells against cisplatin or gefitinib treatment. ZNF32 overexpression in AC cells conferred resistance to EGFR (epidermal growth factor receptor) inhibitors by enhancing MEK/ERK activation. Moreover, ZNF32 was found to directly bind to the TGF-βR2 (transforming growth factor-beta receptor 2) promoter to promote its expression, and ZNF32-induced resistance was mediated by enhancing TGF-βR2 expression and activating the TGF-βR2/SMAD2 pathway. In both a mouse model and ex vivo cultured patient samples, a high level of ZNF32 expression was closely associated with worse overall survival and cisplatin resistance. ZNF32 appears to be a potential inducer of drug resistance that could increase the expression of the drug resistance-associated gene TGF-βR2 and subsequently facilitate the induction of drug resistance during both conventional chemotherapy and novel target therapy. Thus, ZNF32-associated target therapy is a potential novel adjuvant therapy that might effectively prevent the occurrence of multidrug resistance (MDR) during chemotherapy and improve the survival of patients with AC. Nature Publishing Group 2016-10 2016-10-20 /pmc/articles/PMC5133992/ /pubmed/27763636 http://dx.doi.org/10.1038/cddis.2016.328 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Li, Jun Ao, Jie Li, Kai Zhang, Jie Li, Yanyan Zhang, Le Wei, Yuyan Gong, Di Gao, Junping Tan, Weiwei Huang, Lugang Liu, Lunxu Lin, Ping Wei, Yuquan ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma |
title | ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma |
title_full | ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma |
title_fullStr | ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma |
title_full_unstemmed | ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma |
title_short | ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma |
title_sort | znf32 contributes to the induction of multidrug resistance by regulating tgf-β receptor 2 signaling in lung adenocarcinoma |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133992/ https://www.ncbi.nlm.nih.gov/pubmed/27763636 http://dx.doi.org/10.1038/cddis.2016.328 |
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