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Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma

Authors Wang J, Li M, Wang Y, Liu X

Received 26 September 2015

Accepted for publication 23 December 2015

Published 7 March 2016 Volume 2016:9 Pages 1221—1230

DOI https://doi.org/10.2147/OTT.S97211

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ram Prasad

Peer reviewer comments 3

Editor who approved publication: Dr William Cho

Jiye Wang,1 Mi Li,2 Yun Wang,3 Xiaoping Liu4

1The Criminal Science and Technology Department, Zhejiang Police College, Hangzhou, Zhejiang Province, 2Department of Nursing, Shandong College of Traditional Chinese Medicine College, Yantai, Shandong Province, 3Office Department of Gastroenterology, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, Shanxi Province, 4Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Shanghai, People’s Republic of China

Abstract: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death worldwide, characterized by a high invasiveness and resistance to normal anticancer treatments. The need to develop new therapeutic agents for HCC is urgent. Here, we developed a bioinformatics method to identify potential novel drugs for HCC by integrating HCC-related and drug-affected subpathways. By using the RNA-seq data from the TCGA (The Cancer Genome Atlas) database, we first identified 1,763 differentially expressed genes between HCC and normal samples. Next, we identified 104 significant HCC-related subpathways. We also identified the subpathways associated with small molecular drugs in the CMap database. Finally, by integrating HCC-related and drug-affected subpathways, we identified 40 novel small molecular drugs capable of targeting these HCC-involved subpathways. In addition to previously reported agents (ie, calmidazolium), our method also identified potentially novel agents for targeting HCC. We experimentally verified that one of these novel agents, prenylamine, induced HCC cell apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, an acridine orange/ethidium bromide stain, and electron microscopy. In addition, we found that prenylamine not only affected several classic apoptosis-related proteins, including Bax, Bcl-2, and cytochrome c, but also increased caspase-3 activity. These candidate small molecular drugs identified by us may provide insights into novel therapeutic approaches for HCC.

Keywords: subpathways, hepatocellular carcinoma, small molecules, network

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