HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes

PURPOSE: Hepatocyte growth factor (HGF)/Met signaling plays critical roles in pancreatic ductal adenocarcinoma (PDA) development and progression and is considered a potential therapeutic target for this disease. However, the mechanism of aberrant activation of HGF/Met signaling and resistance to Met...

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Autores principales: Cui, Jiujie, Xia, Tian, Xie, Dacheng, Gao, Yong, Jia, Zhiliang, Wei, Daoyan, Wang, Liang, Huang, Suyun, Quan, Ming, Xie, Keping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985506/
https://www.ncbi.nlm.nih.gov/pubmed/26876216
http://dx.doi.org/10.1038/onc.2016.14
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author Cui, Jiujie
Xia, Tian
Xie, Dacheng
Gao, Yong
Jia, Zhiliang
Wei, Daoyan
Wang, Liang
Huang, Suyun
Quan, Ming
Xie, Keping
author_facet Cui, Jiujie
Xia, Tian
Xie, Dacheng
Gao, Yong
Jia, Zhiliang
Wei, Daoyan
Wang, Liang
Huang, Suyun
Quan, Ming
Xie, Keping
author_sort Cui, Jiujie
collection PubMed
description PURPOSE: Hepatocyte growth factor (HGF)/Met signaling plays critical roles in pancreatic ductal adenocarcinoma (PDA) development and progression and is considered a potential therapeutic target for this disease. However, the mechanism of aberrant activation of HGF/Met signaling and resistance to Met inhibition in PDA remains unclear. EXPERIMENTAL DESIGN: The mechanistic role of cross-talk between Forkhead box M1 (FOXM1) and HGF/Met signaling in promotion of PDA growth and resistance to Met inhibition was examined using cell culture, molecular biology and mouse models; and the relevance of our experimental and mechanistic findings were validated using human PDA tissues. RESULTS: Met was markedly overexpressed in both PDA cell lines and pancreatic tumor specimens, and the expression of Met correlated directly with that of FOXM1 in human tumor specimens. Mechanistically, FOXM1 bound to the promoter region of the Met gene and transcriptionally increased the expression of Met. Increased expression of FOXM1 enhanced the activation of HGF/Met signaling and its downstream pathways, including RAS/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/AKT, and signal transducer and activator of transcription 3. Furthermore, activation of HGF/Met signaling increased the expression and transcriptional activity of FOXM1, and the cross-talk between FOXM1 and HGF/Met signaling promoted PDA growth and resistance to Met inhibition. CONCLUSIONS: Collectively, our findings identified a positive feedback loop formed by FOXM1 and HGF/Met and revealed that this loop is a potentially effective therapeutic target for PDA.
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spelling pubmed-49855062016-09-22 HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes Cui, Jiujie Xia, Tian Xie, Dacheng Gao, Yong Jia, Zhiliang Wei, Daoyan Wang, Liang Huang, Suyun Quan, Ming Xie, Keping Oncogene Article PURPOSE: Hepatocyte growth factor (HGF)/Met signaling plays critical roles in pancreatic ductal adenocarcinoma (PDA) development and progression and is considered a potential therapeutic target for this disease. However, the mechanism of aberrant activation of HGF/Met signaling and resistance to Met inhibition in PDA remains unclear. EXPERIMENTAL DESIGN: The mechanistic role of cross-talk between Forkhead box M1 (FOXM1) and HGF/Met signaling in promotion of PDA growth and resistance to Met inhibition was examined using cell culture, molecular biology and mouse models; and the relevance of our experimental and mechanistic findings were validated using human PDA tissues. RESULTS: Met was markedly overexpressed in both PDA cell lines and pancreatic tumor specimens, and the expression of Met correlated directly with that of FOXM1 in human tumor specimens. Mechanistically, FOXM1 bound to the promoter region of the Met gene and transcriptionally increased the expression of Met. Increased expression of FOXM1 enhanced the activation of HGF/Met signaling and its downstream pathways, including RAS/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/AKT, and signal transducer and activator of transcription 3. Furthermore, activation of HGF/Met signaling increased the expression and transcriptional activity of FOXM1, and the cross-talk between FOXM1 and HGF/Met signaling promoted PDA growth and resistance to Met inhibition. CONCLUSIONS: Collectively, our findings identified a positive feedback loop formed by FOXM1 and HGF/Met and revealed that this loop is a potentially effective therapeutic target for PDA. 2016-02-15 2016-09-08 /pmc/articles/PMC4985506/ /pubmed/26876216 http://dx.doi.org/10.1038/onc.2016.14 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Cui, Jiujie
Xia, Tian
Xie, Dacheng
Gao, Yong
Jia, Zhiliang
Wei, Daoyan
Wang, Liang
Huang, Suyun
Quan, Ming
Xie, Keping
HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes
title HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes
title_full HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes
title_fullStr HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes
title_full_unstemmed HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes
title_short HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes
title_sort hgf/met and foxm1 form a positive feedback loop and render pancreatic cancer cells resistance to met inhibition and aggressive phenotypes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985506/
https://www.ncbi.nlm.nih.gov/pubmed/26876216
http://dx.doi.org/10.1038/onc.2016.14
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