Project description:During embryogenesis, Hepatocyte Growth Factor (HGF) elicits a distinctive morphogenetic program, the invasive growth, by the activation of MET, whose aberrant activation in cancer drives metastatic progression. Aim of this work is to define and characterize the transcriptional signature of invasive growth, and to verify its activation in human cancers. Global expression profiling was carried out on mouse liver stem/progenitor cells (MLP-29) stimulated for different times, one, six and twenty-four hours, in vitro with HGF to define the invasive growth signature. Meta-analysis of human cancer microarray data was carried out to dissect the transcriptional modules of the invasive growth that are aberrantly activated during carcinogenesis of hepatocellular carcinoma. Differential expression analysis identified 2643 regulated genes by HGF, the invasive growth signature, subdivided in 11 gene expression clusters revealing waves of time coded transcriptional regulation. Those waves have been in-silico associated with the regulative role of the transcriptional unit of Rela/Nfkbia and Fos/Jun and biological features recapitulating the physiological invasive growth phenotype observed in cell line, such as cell motility and scattering, cellular proliferation and protection from apoptosis, cytoskeletal rearangement. Genomic meta-analysis on hepatocellular carcinoma identified of a core genes set (323 gene symbols), consistently regulated between MLP-29 and human tumors and significantly associated with cancer aggressiveness and metastasis p.val < 1*10-6, HR=5.404 CI= 2.570-11.365. The invasive growth signature recapitulates the physiopatological program driven by the stimulation of HGF in normal embryonic liver cells and its activity is observed in HCC as well as in several other tumors. This signature is associated with neoplastic progression and reliably predicts human HCC disease outcome, suggesting the involvement of the invasive growth and cancer in cancer progression. These results prompt the future application of anti-met target therapies in HCC and the application of the signature for both prognostic and predictive purposes.
Project description:Mueller2015 - Hepatocyte proliferation, T160
phosphorylation of CDK2
This model is described in the article:
T160-phosphorylated CDK2
defines threshold for HGF-dependent proliferation in primary
hepatocytes.
Mueller S, Huard J, Waldow K, Huang
X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S,
Klingmüller U, Schilling M.
Mol. Syst. Biol. 2015; 11(3): 795
Abstract:
Liver regeneration is a tightly controlled process mainly
achieved by proliferation of usually quiescent hepatocytes. The
specific molecular mechanisms ensuring cell division only in
response to proliferative signals such as hepatocyte growth
factor (HGF) are not fully understood. Here, we combined
quantitative time-resolved analysis of primary mouse hepatocyte
proliferation at the single cell and at the population level
with mathematical modeling. We showed that numerous G1/S
transition components are activated upon hepatocyte isolation
whereas DNA replication only occurs upon additional HGF
stimulation. In response to HGF, Cyclin:CDK complex formation
was increased, p21 rather than p27 was regulated, and Rb
expression was enhanced. Quantification of protein levels at
the restriction point showed an excess of CDK2 over CDK4 and
limiting amounts of the transcription factor E2F-1. Analysis
with our mathematical model revealed that T160 phosphorylation
of CDK2 correlated best with growth factor-dependent
proliferation, which we validated experimentally on both the
population and the single cell level. In conclusion, we
identified CDK2 phosphorylation as a gate-keeping mechanism to
maintain hepatocyte quiescence in the absence of HGF.
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Project description:we identified the differentially expressed genes (DEGs) in hiPSC-NPCs exposed to conditioned media from hiPSC-NPCs transfected with hepatocyte growth factor (HGF-NPCs) by transcriptome analysis.
Project description:we identified the differentially expressed genes (DEGs) in hiPSC-NPCs exposed to conditioned media from hiPSC-NPCs transfected with hepatocyte growth factor (HGF-NPCs) by transcriptome analysis.
Project description:Transcription profile of HepG2 cells treated with hepatocyte growth factor and control cells Two condition experiment, Hep G2 vs. Hep G2-HGF. Biological replicates: 1 control and 1 HGF-treated (no replication)