Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA253134 | ENA |
REPOSITORIES: ENA
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Project description:HGF has been reported to have both positive and negative effects on carcinogenesis. Here we show that the loss of c-Met signaling in hepatocytes enhanced rather than suppressed the early stages of chemical hepatocarcinogenesis. c-Met conditional knockout mice (c-metfl/fl, AlbCre+/-; MetLivKO) treated with N-nitrosodiethylamine (DEN) developed significantly more and bigger tumors and with a shorter latency as compared with control (wt/wt, AlbCre+/-; Cre-Ctrl) mice. Accelerated tumor development was associated with increased rate of cell proliferation and prolonged activation of epidermal growth factor receptor (EGFR) signaling. MetLivKO livers treated with DEN also displayed elevated lipid peroxidation, decreased ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and upregulation of superoxide dismutase 1 (Sod1) and heat shock protein 70 (Hsp70), all consistent with increased oxidative stress. Likewise, gene expression profiling performed at 3 and 5 months after DEN treatment revealed upregulation of genes associated with cell proliferation and stress responses in c-Met mutant livers. The negative effects of c-Met-deficiency were reversed by chronic oral administration of anti-oxidant N-acetylcysteine (NAC). NAC blocked the EGFR activation and reduced the DEN-initiated hepatocarcinogenesis to the levels of Cre-Ctrl mice. These results argue that intact HGF/c-Met signaling is essential for maintaining normal redox homeostasis in the liver and has tumor suppressor effect(s) during the early stages of DEN-induced hepatocarcinogenesis. Keywords: compound treatment design To address a role for c-Met in liver carcinogenesis, we employed a hepatocyte specific c-Met conditional knockout mouse model generated in our laboratory. Mice received a single intraperitoneal injection of 10 µg/g body weight of N-nitrosodiethylamine (DEN) (Sigma-Aldrich, Inc., St. Louis, MO, USA) at 14 days of age. Livers were examined at 3 and 5 months after DEN injection. Expression profiling was conducted on five animals from each genotype per time point. Total RNA pooled from five wild-type B6/129 strain mouse livers was used as universal hybridization reference. All experiments were performed in duplicates following a dye-swapping design. Arrays were scanned with a GenePix 4000A scanner (Axon Instruments Ltd., Burlingame, CA) in a way to achieve optimal signal intensity at both channels with less than 1% saturated spots. After excluding the invalid features, all arrays were normalized to the 50th percentile of the median signal intensity using the mAdb data analysis suite (http://nciarray.nci.nih.gov/). Unsupervised cluster analysis was performed with the Cluster and TreeView programs (http://rana.lbl.gov/EisenSoftware.htm). The BRB ArrayTools V3.3.0 software package (Biometric Research Branch, National Cancer Institute; http://linus.nci.nih.gov/BRB-ArrayTools.html) was used for the supervised comparison. Differentially expressed genes were selected using a univariate 2-sample t-test (P<0.001) with a random variance model (15). Functional classification of the significant genes was based on the Gene Ontology (GO) annotations (www.geneontology.org).
2008-08-09 | E-GEOD-8747 | biostudies-arrayexpress
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.
2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET.
2014-06-01 | GSE31852 | GEO
Project description:HGF has been reported to have both positive and negative effects on carcinogenesis. Here we show that the loss of c-Met signaling in hepatocytes enhanced rather than suppressed the early stages of chemical hepatocarcinogenesis. c-Met conditional knockout mice (c-metfl/fl, AlbCre+/-; MetLivKO) treated with N-nitrosodiethylamine (DEN) developed significantly more and bigger tumors and with a shorter latency as compared with control (wt/wt, AlbCre+/-; Cre-Ctrl) mice. Accelerated tumor development was associated with increased rate of cell proliferation and prolonged activation of epidermal growth factor receptor (EGFR) signaling. MetLivKO livers treated with DEN also displayed elevated lipid peroxidation, decreased ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and upregulation of superoxide dismutase 1 (Sod1) and heat shock protein 70 (Hsp70), all consistent with increased oxidative stress. Likewise, gene expression profiling performed at 3 and 5 months after DEN treatment revealed upregulation of genes associated with cell proliferation and stress responses in c-Met mutant livers. The negative effects of c-Met-deficiency were reversed by chronic oral administration of anti-oxidant N-acetylcysteine (NAC). NAC blocked the EGFR activation and reduced the DEN-initiated hepatocarcinogenesis to the levels of Cre-Ctrl mice. These results argue that intact HGF/c-Met signaling is essential for maintaining normal redox homeostasis in the liver and has tumor suppressor effect(s) during the early stages of DEN-induced hepatocarcinogenesis. Keywords: compound treatment design
2008-08-09 | GSE8747 | GEO
Project description:Receptor tyrosine kinases MET and EGFR are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also help in the early part of the process. Regeneration employs effective redundancy schemes to compensate for missing signals. Elimination of any single signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling abolishes liver regeneration, prevents restoration of liver mass and leads to liver decompensation. Our results demonstrate that liver function is dependent on synchronous availability of signaling from these two pathways. The study shows that MET and EGFR separately control many non-overlapping signaling endpoints, allowing for compensation when only one of the signals is blocked. The combined elimination of the signals however was not tolerated. The results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. We used microarrays to detail the global programme of gene expression in METKO-canertinib mouse liver following a partial hepatectomy
2016-10-27 | GSE77867 | GEO
Project description:MET and EGFR receptor tyrosine kinases are crucial for liver regeneration and normal hepatocyte function. Recently we demonstrated that in mice, combined inhibition of these two signaling pathways abolished liver regeneration following hepatectomy, with subsequent hepatic failure and death at 15-18 days post-resection. Morbidity was associated with distinct and specific alterations in important downstream signaling pathways that led to a decrease in hepatocyte volume, reduced proliferation, and shutdown of many essential hepatocyte functions such as fatty acid synthesis, urea cycle, and mitochondrial functions. In the present study we explore the role of MET and EGFR signaling in resting mouse livers that are not subjected to hepatectomy. Mice with combined disruption of MET and EGFR signaling (Delta MET + EGFRi) were noticeably sick by 10 day and died at 12-14 days. Delta MET + EGFRi mice showed decreased liver to body weight ratios, increased apoptosis in non-parenchymal cells, impaired liver metabolic functions, and activation of distinct, downstream signaling pathways related to inflammation, cell death, and survival. Conclusion: The present study demonstrates that in addition to controlling the regenerative response, MET and EGFR synergistically control baseline liver homeostasis in normal mice in such a way that their combined disruption leads to liver failure and death. We used microarrays to detail the global programme of gene expression in Delta MET + EGFRi mice liver vs control mice liver
2018-07-09 | GSE116307 | GEO
Project description:MET expression is elevated in a majority of human skin cancers but its contributions to pathogenesis have not been evaluated. In a mouse model of constitutive overexpression of HGF (MT-HGF), the incidence of squamous cell skin tumors induced by initiation with 7,12-dimethylbenz(a)anthracene (DMBA) followed by exposure to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) is increased fivefold over control groups. Half of these tumors carry Hras1 or Kras mutations. Without DMBA initiation, tumors also erupt on MT-HGF mouse skin but only when TPA promotion is enhanced by crossing these mice with mice overexpressing cutaneous PKCα. None of these tumors have Ras mutations. In culture, MT-HGF keratinocytes share identical MET mediated phenotypic and biochemical features with wildtype keratinocytes transformed by oncogenic RAS. In both cell types, these common features of initiated keratinocytes arise from autocrine activation of EGFR through elevated expression and release of EGFR ligands. Inhibition of EGFR ablates the initiated signature of MT-HGF keratinocytes in vitro and causes regression of MT-HGF induced tumors in vivo. Global gene expression data indicate that MT-HGF and RAS transformed keratinocytes share largely an identical profile of over 5000 mRNAs. Gene ontology analysis reveals the most affected concordant signature is enriched for functions relevant to tissue development and response to wounding, accompanied by cytokine and growth factor activity, and peptidase and endopeptidase activity previously not linked to initiated keratinocytes. Furthermore, gene co-expression analysis in skin cancer patients revealed a core RAS/MET co-expression network considerably activated in pre cancerous and cancerous lesions. Thus MET activation though EGFR contributes to human cutaneous cancers, and inhibitors could be efficacious in advanced lesions such as those seen in transplant recipient patients. In this dataset with provide gene expression data from primary mouse keratinocytes in culture.
2016-06-21 | GSE58671 | GEO
Project description:Constitutive MET signaling promotes invasiveness in primary and recurrent GBM; however, current MET-targeting strategies lack of effective biomarkers for selecting suitable patients for treatment. Here, we identified a predictive signature potentially valuable for indicating vulnerability to MET-targeted therapy in GBM. The use of both human and mouse gene expression microarrays showed that MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall they impede tumor growth by inhibiting cell cycle progression. Notably, GBM tumors with EGFRamp that showed resistance to erlotinib treatment also showed activation of the MET pathway, suggesting that a combination of EGFR and MET inhibitors may overcome or prevent such resistance in patients with EGFRamp GBM.
2016-01-05 | GSE64667 | GEO
Project description:Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4- based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.
2023-10-09 | PXD025361 | Pride