title: 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: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
authors: Qian
authors: Q
authors: Sun
authors: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
authors: Ronghua
authors: R
authors: Wang
authors: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
authors: Yan
authors: Y
authors: Wang
authors: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
authors: Jing
authors: J
authors: Luo
authors: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
authors: Peng
authors: P
authors: Wang
authors: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
authors: Bin
authors: B
authors: Cheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics; D053453:Caspase 9 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050687:E2F1 Transcription Factor / Q000096:biosynthesis; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006515:Hepatitis B virus / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000188:drug therapy; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D053148:Caspase 3; D053453:Caspase 9