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Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop

In the present study, we demonstrate that prolonged treatment by trastuzumab induced resistance of NCI-N87 gastric cancer cells to trastuzumab. The resistant cells possessed typical characteristics of epithelial to mesenchymal transition (EMT)/cancer stem cells and acquired more invasive and metasta...

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Autores principales: Yang, Zhengyan, Guo, Liang, Liu, Dan, Sun, Limin, Chen, Hongyu, Deng, Que, Liu, Yanjun, Yu, Ming, Ma, Yuanfang, Guo, Ning, Shi, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467134/
https://www.ncbi.nlm.nih.gov/pubmed/25669984
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author Yang, Zhengyan
Guo, Liang
Liu, Dan
Sun, Limin
Chen, Hongyu
Deng, Que
Liu, Yanjun
Yu, Ming
Ma, Yuanfang
Guo, Ning
Shi, Ming
author_facet Yang, Zhengyan
Guo, Liang
Liu, Dan
Sun, Limin
Chen, Hongyu
Deng, Que
Liu, Yanjun
Yu, Ming
Ma, Yuanfang
Guo, Ning
Shi, Ming
author_sort Yang, Zhengyan
collection PubMed
description In the present study, we demonstrate that prolonged treatment by trastuzumab induced resistance of NCI-N87 gastric cancer cells to trastuzumab. The resistant cells possessed typical characteristics of epithelial to mesenchymal transition (EMT)/cancer stem cells and acquired more invasive and metastatic potentials both in vitro and in vivo. Long term treatment with trastuzumab dramatically inhibited the phosphorylation of Akt, but triggered the activation of STAT3. The level of IL-6 was remarkably increased, implicating that the release of IL-6 that drives the STAT3 activation initiates the survival signaling transition. Furthermore, the Notch activities were significantly enhanced in the resistant cells, companied by upregulation of the Notch ligand Jagged-1 and the Notch responsive genes Hey1 and Hey2. Inhibiting the endogenous Notch pathway reduced the IL-6 expression and restored the sensitivities of the resistant cells to trastuzumab. Blocking of the STAT3 signaling abrogated IL-6-induced Jagged-1 expression, effectively inhibited the growth of the trastuzumab resistant cells, and enhanced the anti-tumor activities of trastuzumab in the resistant cells. These findings implicate that the IL-6/STAT3/Jagged-1/Notch axis may be a useful target and that combination of the Notch or STAT3 inhibitors with trastuzumab may prevent or delay clinical resistance and improve the efficacy of trastuzumab in gastric cancer.
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spelling pubmed-44671342015-06-22 Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop Yang, Zhengyan Guo, Liang Liu, Dan Sun, Limin Chen, Hongyu Deng, Que Liu, Yanjun Yu, Ming Ma, Yuanfang Guo, Ning Shi, Ming Oncotarget Research Paper In the present study, we demonstrate that prolonged treatment by trastuzumab induced resistance of NCI-N87 gastric cancer cells to trastuzumab. The resistant cells possessed typical characteristics of epithelial to mesenchymal transition (EMT)/cancer stem cells and acquired more invasive and metastatic potentials both in vitro and in vivo. Long term treatment with trastuzumab dramatically inhibited the phosphorylation of Akt, but triggered the activation of STAT3. The level of IL-6 was remarkably increased, implicating that the release of IL-6 that drives the STAT3 activation initiates the survival signaling transition. Furthermore, the Notch activities were significantly enhanced in the resistant cells, companied by upregulation of the Notch ligand Jagged-1 and the Notch responsive genes Hey1 and Hey2. Inhibiting the endogenous Notch pathway reduced the IL-6 expression and restored the sensitivities of the resistant cells to trastuzumab. Blocking of the STAT3 signaling abrogated IL-6-induced Jagged-1 expression, effectively inhibited the growth of the trastuzumab resistant cells, and enhanced the anti-tumor activities of trastuzumab in the resistant cells. These findings implicate that the IL-6/STAT3/Jagged-1/Notch axis may be a useful target and that combination of the Notch or STAT3 inhibitors with trastuzumab may prevent or delay clinical resistance and improve the efficacy of trastuzumab in gastric cancer. Impact Journals LLC 2014-12-31 /pmc/articles/PMC4467134/ /pubmed/25669984 Text en Copyright: © 2015 Yang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Yang, Zhengyan
Guo, Liang
Liu, Dan
Sun, Limin
Chen, Hongyu
Deng, Que
Liu, Yanjun
Yu, Ming
Ma, Yuanfang
Guo, Ning
Shi, Ming
Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop
title Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop
title_full Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop
title_fullStr Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop
title_full_unstemmed Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop
title_short Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop
title_sort acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of il-6/stat3/jagged-1/notch positive feedback loop
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467134/
https://www.ncbi.nlm.nih.gov/pubmed/25669984
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