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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1782448069320638464 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4985506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT cuijiujie hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT xiatian hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT xiedacheng hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT gaoyong hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT jiazhiliang hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT weidaoyan hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT wangliang hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT huangsuyun hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT quanming hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes AT xiekeping hgfmetandfoxm1formapositivefeedbackloopandrenderpancreaticcancercellsresistancetometinhibitionandaggressivephenotypes |