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| 1 | Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3显示文摘AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC).METHODS: Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC model.RESULTS: Sorafenib decreased STAT3 phosphorylationat the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phosphatase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib signifi cantly inhibited STAT3 activity, reducing tumor growth and metastasis.CONCLUSION: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation. | Fang-Ming Gu, Quan-Lin Li, Qiang Gao, Jia-Hao Jiang, Xiao-Yong Huang, Jin-Feng Pan, Jia Fan, Jian ZhouFang-Ming Gu, Quan-Lin Li, Qiang Gao, Jia-Hao Jiang, Xiao-Yong Huang, Jin-Feng Pan, Jia Fan, Jian Zhou, Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai 200032, China Author contributions: Gu FM, Li QL and Gao Q contributed equally to this work Gu FM and Li QL performed the experi- ments and interpretation of the data and statistical analysis Zhou J and Gao Q contributed to the conception and design of the study Gu FM, Gao Q, Li QL and Zhou J wrote the manuscript Jiang JH, Huang XY, Pan JF and Fan J made substantial contri- bution to the design and conception of the study and interpreta- tion of data all authors read and approved the f inal manuscript. | 2011 | World Journal of Gastroenterology2011，17，34： | 18 |
| 2 | Basic previous term hydrol- ysis next term 2- fluoro-1,3,4,6-tetra-O-acetyl-image-glu- cose in the preparation of 2-显示文摘 | Fuchtner F Steinbach J Mading P | 1996 | Appl Radiat Isot1996，47，： | 1 |
| 3 | Homogeneous catalysts based on silane dendrimers functionalized with arylnickel(Ⅱ) complex显示文摘 | Knapen J W J van der Made A W de Wilde J C | | 0，，： | 1 |
| 4 | Observations on the different methods of processing on the bacterial contaminants of bovine and ovine tripe显示文摘 | van der MADE H N van STADEN J J | 1978 | Onderstepoort Journal of Veterinary Research1978，45，： | 1 |
| 5 | Changes in reactive surface area during limestone dissolution: An experimental and modelling study显示文摘 | Noiriel C Luquot L Made B Raimbault L Gouze P van der Lee J | 2009 | Chem Geol2009，265，12： | 1 |
| 6 | Ventilation strategy using low tidal volumes,recruitment maneuvers,and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome:a randomized controlled trial显示文摘 | MADE M O COOK D J GUYATT G H | 2008 | JAMA2008，299，6： | 1 |
| 7 | Expression of Ecadherin,β-catenin and Ki-67 antigen and their reciprocal relationships in mammary adenocarcinomas in bitches显示文摘 | MARCIN N JANUSZ A MADE J | 2007 | ET Cytobiologica2007，3，45： | 1 |
| 8 | Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with Vitamin C therapy 显示文摘 | Chambers JC McGregor A Made J J | 1999 | Circulation1999，99，11： | 1 |
| 9 | BioMagResBank显示文摘 | Ulrich E L Akutsu H Doreleijers J F Harano Y Ioannidis Y E Lin J Livny M Mading S Maziuk D Miller Z Nakatani E Schulte C F Tolmie D E Kent Wenger R Yao H Markley J L | | 0，，1： | 1 |
| 10 | Hematopoietic NF-kappaB1 deficiency resuhs in small atheroselerotic lesions with an inflammatory phenotype 显示文摘 | Kanters E Gijbels M J Ingeborg van der Made | 2004 | Blood2004，103，3： | 1 |
| 11 | Basic Hydrolysis of 2--fluoro-1,3,4,6-tetra-oacetyl-D-glucose in the Preparation of 2--fluoro-2-deoxy-D-glucose显示文摘 | Steinbach J Mading P | 1996 | Appl Radiat Isto1996，47，： | 1 |
| 12 | Clade-Specific 16S ribosomal DNA oligonucleotides reveal the predominance of a single marine synechococcus clade throughout a stratified water column in the red sea 显示文摘 | Fuller N J Made D Partensky F | 2003 | Applied and Environmental Microbiology2003，69，5： | 1 |
| 13 | Basic hydrolysis of 2- -fluoro-1,3,4,6-tetra-O-acetyl-D-glucose in the preparation of 2--fluoro-2-deoxy-D-glucose显示文摘 | Fuchtner F Steinbach J Mading P | 1996 | Appl Radiat Isot1996，47，1： | 1 |
| 14 | Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis 显示文摘 | Roderick J P Made D B Kurt H | 2004 | The Journal of Clinical Investigation2004，114，3： | 1 |
| 15 | The influence of testosterone combined with a PDE5-inhibitor on cognitive, af- fective, and physiological sexual functioning in women suffering from sexual dysfunction显示文摘 | Van der Made F Bloemers J Yassem WE et J | 2009 | J Sex Med2009，6，3： | 1 |
| 16 | Basic Hydrolysis of 2-fluoro-1,3,4,6-tetra-O-acetyl-D-glucose in the Preparation of 2-fluoro-2-deoxy-D-glucose显示文摘 | Fuchtner F Steinbach J Mading P | 1996 | Appl Radiat Isto1996，47，： | 1 |
| 17 | Chemotherapy for angiosarcoma of the breast: A case report of 30 year survival and analysis of the literature显示文摘 | Lewis LR Deligdisch L Madeli J | 1994 | Cancer Invest1994，12，20： | 1 |
| 18 | A range chart for European Suidae and Tayasuidae显示文摘 | Made J D | 1989 | Paleont Evol1989，23，： | 1 |
| 19 | European Suidae (Artiodactyla) from the late Miocene onwards显示文摘 | Made J D Moya Sola S | 1989 | Bull Soc Paleont Ital1989，28，： | 1 |
| 20 | Basic Hydrolysis of 2-fluoro-1, 3, 4, 6-tetra-oacetyl-D-glucose in the Preparation of 2-fluoro-2-deoxy-D-glucose 显示文摘 | Fuchtner F Steinbach J Mading P | 1996 | Appl Radiat Istoes1996，47，： | 1 |
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