TITLE

Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets

AUTHOR(S)
Junyan Lu; Hanlin Zeng; Zhongjie Liang; Limin Chen; Liyi Zhang; Hao Zhang; Hong Liu; Hualiang Jiang; Bairong Shen; Ming Huang; Meiyu Geng; Sarah Spiegel; Cheng Luo
PUB. DATE
October 2015
SOURCE
Scientific Reports;10/9/2015, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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.
ACCESSION #
110327890

 

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