HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes

Abstract

PurposeHepatocyte 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 DesignThe 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.ResultsMet 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.ConclusionsCollectively, 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.

Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma

“…The latter has been repeatedly implicated in drug-resistant solid cancers; e.g., in retinoblastoma [ 35 ], bladder cancer [ 36 ] and colorectal cancer [ 37 ], in which the heightened drug-efflux activity could be functionally linked to FOXM1-dependent upregulation of ABCC4, ABCG2 and ABCC10, respectively. Also playing a role may be other pathways of drug resistance that operate in solid tumors [ 38 ]; e.g., inhibition of ubiquitination-dependent FOXM1 degradation via interacting proteins, such as OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1) [ 39 ]; crosstalk of FOXM1 with other cellular signal transduction pathways, such as HGF / Met (hepatocyte growth factor / Met proto-oncogene, receptor tyrosine kinase) [ 40 ] and AKT (AKT serine / threonine kinase 1) [ 41 ]; and metabolic changes that effect increased oxidative defense capacity, as seen in radio-resistant head and neck squamous cell carcinoma [ 42 ]. Targeting the interactions and pathways described above – perhaps in conjunction with targeting FOXM1 directly using established [ 43 ] or emerging [ 44 ] small-drug inhibitors – may afford the re-sensitization of relapsed FOXM1 High myeloma to Bz and other drugs that were effective at earlier stages of myeloma therapy.…”

TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

“…(5,28) Our previous microarray data and various other studies indicated that both EGFR and MET can regulate FOXM1 expression. (6,(23)(24)(25)(26)(27) Here we report that TCPOBOP-driven FOXM1 induction and its downstream gene network activation was remarkably impaired in [MET KO + EGFRi] mice, which might contribute to attenuated proliferation in our model. Conversely, the inverse phenotype to our model (i.e., increased proliferation but reduced expression of drug metabolic enzymes) previously reported in β-catenin KO mice following TCPOBOP treatment was attributed to increased FOXM1 levels.…”

“…Our previous data and several other reports indicated that both MET and EGFR can regulate an important transcription factor, FOXM1, which governs transcription of genes important for DNA replication and mitosis. (6,(23)(24)(25)(26)(27) FOXM1 is considered to be critical for inducing TCPOBOP-mediated hepatocyte proliferation. (3,5,14,16,22,28) Consistent with these previous reports, FOXM1 was remarkably induced by TCPOBOP at all of the time points in control mice with peak induction (10-fold) coinciding with the time point of peak proliferation (day 2) ( Fig.…”

Cross‐species analysis of the canine and human bladder cancer transcriptome and exome

“…Because of previous reports that elevated expression of the tyrosine kinase proto‐oncogene MET is a marker of tumor aggressiveness in bladder cancer and has been proposed as both a biomarker and a therapeutic target, we investigated MET expression in the canine bladder mRNA‐seq dataset. We found that MET is 4.6‐fold upregulated in canine bladder cancer versus normal bladder samples ( P < .05, Welch's t‐ test on log 2 ‐transformed, sample‐normalized data; see Methods) (Supporting Information Fig.…”