title: Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma.
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.
authors.affiliation: The Criminal Science and Technology Department, Zhejiang Police College, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Nursing, Shandong College of Traditional Chinese Medicine College, Yantai, Shandong Province, People's Republic of China.
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.affiliation: Office Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shanxi Province, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Shanghai, People's Republic of China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
keywords: hepatocellular carcinoma; network; small molecules; subpathways