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2016 ; 35
(36
): 4708-18
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer
cells resistance to Met inhibition and aggressive phenotypes
#MMPMID26876216
Cui J
; Xia T
; Xie D
; Gao Y
; Jia Z
; Wei D
; Wang L
; Huang S
; Quan M
; Xie K
Oncogene
2016[Sep]; 35
(36
): 4708-18
PMID26876216
show ga
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.