title: HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes.
abstract: Hepatocyte growth factor (HGF)/Met signaling has 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. 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. 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 retrovirus-associated DNA sequences/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. 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.
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Gastroenterology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: T
authors.initials: T
authors.lastname: Xia
authors.affiliation: Department of Oncology, Shanghai Tongji University Affiliated East Hospital, Shanghai, People's Republic of China.
authors.forename: D
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Oncology, Shanghai Tongji University Affiliated East Hospital, Shanghai, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Oncology, Shanghai Tongji University Affiliated East Hospital, Shanghai, People's Republic of China.
authors.forename: M
authors.initials: M
authors.lastname: Quan
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Xie
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met