Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma.

Abstract	Hepatocellular carcinoma (HCC) is a highly lethal cancer with increasing worldwide incidence, and there are few therapeutics options available for patients with HCC. Thus, novel therapeutic targets for this disease are desperately needed. Chronic infection with hepatitis B virus (HBV) is the major risk factor for the development of HCC, while hepatitis B virus X protein (HBx) is essential for HBV-associated HCC. Based on our previous studies showing that HBx promoted hepatocarcinogenesis of the human non-tumor hepatic cell line L02 and activated Notch1 signaling, Notch1 short hairpin RNA (shRNA) was utilized to inhibit Notch1 mRNA in the present study. We observed that Notch1 shRNA inhibited cell proliferation together with decreased activity of the Notch1 pathway in vitro, and also markedly suppressed tumor formation of L02/HBx cells in a BALB/c nude mouse model in vivo. Furthermore, the blockade of Notch1 was capable of arresting the cell cycle in the G0/G1 phase through the downregulation of CyclinD1, CDK4, E2F1 and the upregulation of p21 and Rb, while all of these factors were involved in the CyclinD1/CDK4 pathway. Inhibition of Notch1 by shRNA markedly promoted the apoptosis of L02/HBx cells via the caspase-9-caspase-3 pathway. These data suggest that inhibition of Notch1 impairs the growth of human HBx-transformed L02 cells, and Notch1 may be a putative therapeutic target for human HBx-associated HCC.
Authors	Qian Sun, Ronghua Wang, Yan Wang, Jing Luo, Peng Wang, Bin Cheng
Journal	Oncology reports (Oncol Rep) Vol. 31 Issue 2 Pg. 933-9 (Feb 2014) ISSN: 1791-2431 [Electronic] Greece
PMID	24336972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cyclin-Dependent Kinase Inhibitor p21 E2F1 Transcription Factor E2F1 protein, human NOTCH1 protein, human RNA, Messenger RNA, Small Interfering Receptor, Notch1 Retinoblastoma Protein Trans-Activators Viral Regulatory and Accessory Proteins hepatitis B virus X protein Cyclin D1 CDK4 protein, human Cyclin-Dependent Kinase 4 Caspase 3 Caspase 9
Topics	Animals Apoptosis (genetics) Carcinoma, Hepatocellular (genetics) Caspase 3 (genetics) Caspase 9 (genetics) Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic Cyclin D1 (biosynthesis) Cyclin-Dependent Kinase 4 (biosynthesis) Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis) E2F1 Transcription Factor (biosynthesis) G1 Phase Cell Cycle Checkpoints (genetics) Gene Expression Regulation, Neoplastic Hepatitis B virus (pathogenicity) Hepatitis B, Chronic (drug therapy) Humans Liver Neoplasms (genetics) Male Mice Mice, Inbred BALB C Mice, Nude RNA Interference RNA, Messenger (biosynthesis) RNA, Small Interfering Receptor, Notch1 (genetics, metabolism) Retinoblastoma Protein (biosynthesis) Signal Transduction (genetics) Trans-Activators Viral Regulatory and Accessory Proteins Xenograft Model Antitumor Assays

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