Abstract
The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / therapeutic use*
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Ceramides / antagonists & inhibitors
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Ceramides / metabolism
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Colitis / complications
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Colitis / drug therapy*
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Colitis / genetics
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Colitis / pathology
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Colon / drug effects
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Colon / metabolism
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Colon / pathology
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Colonic Neoplasms / complications
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / genetics
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Colonic Neoplasms / pathology
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Computer Simulation
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Gene Expression Regulation, Neoplastic*
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Gene Regulatory Networks / drug effects
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Humans
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Models, Genetic*
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Molecular Targeted Therapy
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Mutation
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Interaction Mapping
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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Ceramides
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Phosphoinositide-3 Kinase Inhibitors
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Proto-Oncogene Proteins c-akt