Project description:Hepatocellular carcinoma (HCC) is a common malignancy with high mortality due to a lack of effective therapies. HCC represents a collection of highly heterogeneous tumor types but a general molecular classification of HCC is lacking. Here, we define three molecular subtypes of HCC that are observed across various independent patient cohorts and profiling platforms. Analysis of the expression signatures indicates that a limited number of pathways and processes drive the clustering of these subtypes. Notably, TGF-beta signaling is a critical factor that distinguishes two subtypes of high-grade tumors, and is associated with early tumor recurrence. Furthermore, both bioinformatics and functional analyses reveal molecular crosstalk between TGF-beta and WNT signaling pathways. These findings suggest that TGF-beta plays a critical role in a subclass of HCC tumors and may enhance WNT pathway activation in the absence of activating mutations in canonical pathway components. This study is an example of how robust molecular subclassification can be used to interrogate molecular abnormalities in the context of human cancer. Experiment Overall Design: Four hepatocellular carcinoma (HCC) cell line samples treated or untreated by TGF-beta
Project description:Wnt/beta-catenin signaling is involved in various aspects of skeletal muscle development and regeneration. Using C2C12 cells, we examined intracellular signaling and gene transcription during myoblast proliferation and differentiation. The results of the present studies suggest that Wnt signaling is interacting with TGF-beta superfamily signaling through Smad activation. Single analysis for each condition (proliferating C2C12 cells, differentiating C2C12 cells, proliferating Wnt4-overexpressing C2C12 subline cells).
Project description:Wnt/beta-catenin signaling is involved in various aspects of skeletal muscle development and regeneration. Using C2C12 cells, we examined intracellular signaling and gene transcription during myoblast proliferation and differentiation. The results of the present studies suggest that Wnt signaling is interacting with TGF-beta superfamily signaling through Smad activation.
Project description:Kim2007 - Crosstalk between Wnt and ERK pathways
Experimental studies have shown that both Wnt and the MAPK pathways are involved in the pathogenesis of various kinds of cancers (eg. colorectal cancer). The crosstalk between the two pathways have also been identified. Here, Kim et al., (2007) have integrated the experimental evidences on crosstalk mechanisms between the two pathways into a pathway model, and have identified the existence of a hidden positive feedback loop and suggest that this positive feedback loop might participate in the pathogenesis of colorectal cancer.
This model is described in the article:
A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways.
Kim D, Rath O, Kolch W, Cho KH.
Oncogene 2007 Jul; 26(31): 4571-4579
Abstract:
The Wnt and the extracellular signal regulated-kinase (ERK) pathways are both involved in the pathogenesis of various kinds of cancers. Recently, the existence of crosstalk between Wnt and ERK pathways was reported. Gathering all reported results, we have discovered a positive feedback loop embedded in the crosstalk between the Wnt and ERK pathways. We have developed a plausible model that represents the role of this hidden positive feedback loop in the Wnt/ERK pathway crosstalk based on the integration of experimental reports and employing established basic mathematical models of each pathway. Our analysis shows that the positive feedback loop can generate bistability in both the Wnt and ERK signaling pathways, and this prediction was further validated by experiments. In particular, using the commonly accepted assumption that mutations in signaling proteins contribute to cancerogenesis, we have found two conditions through which mutations could evoke an irreversible response leading to a sustained activation of both pathways. One condition is enhanced production of beta-catenin, the other is a reduction of the velocity of MAP kinase phosphatase(s). This enables that high activities of Wnt and ERK pathways are maintained even without a persistent extracellular signal. Thus, our study adds a novel aspect to the molecular mechanisms of carcinogenesis by showing that mutational changes in individual proteins can cause fundamental functional changes well beyond the pathway they function in by a positive feedback loop embedded in crosstalk. Thus, crosstalk between signaling pathways provides a vehicle through which mutations of individual components can affect properties of the system at a larger scale.
Figure 6 of the reference publication has been reproduced. The model as such reproduces the plots corresponding to the normal conditions. To obtain simulations under 1) beta-cataenin mutation; set V12=0.846 (two-fold of the beta-catenin synthetic rate than the normal system. i.e. 2*0.426), 2) PP2A mutation; set Vmax4=Vmax5=33.75 (three-fourths of the PP2A activity that the normal system. i.e. (3/4)*45). The simulation was performed using Copasi 4.10 (Build 55).
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Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis with poor prognosis. An aberrant recapitulation of lung developmental genes including transforming growth factor (TGF)-β and WNT has been widely implicated in the abnormal wound healing process following repetitive alveolar epithelial injury during IPF pathogenesis. Extracellular vesicles (EVs) including exosomes and microvesicles have been shown to carry various bioactive molecules and are involved in a variety of physiological and pathological processes. Here, we demonstrate that human bronchial epithelial cell-derived EVs (HBEC EVs) inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling. To ask how HBEC-EVs inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling, miRNA RNA-seq of HBEC-EVs was performed.
Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis with poor prognosis. An aberrant recapitulation of lung developmental genes including transforming growth factor (TGF)-β and WNT has been widely implicated in the abnormal wound healing process following repetitive alveolar epithelial injury during IPF pathogenesis. Extracellular vesicles (EVs) including exosomes and microvesicles have been shown to carry various bioactive molecules and are involved in a variety of physiological and pathological processes. Here, we demonstrate that human bronchial epithelial cell-derived EVs (HBEC EVs) inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling. To ask how HBEC-EVs inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling, miRNA RNA-seq of HBEC-EVs was performed.