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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 | 守恒概念获得的研究显示文摘本研究是继“双语儿童概念获得”实验而作的一项研究。前项研究集中于语言与思维关系的分析,本实验着重观察不同文化背景、不同年龄儿童掌握守恒概念之异同,从而对学习与发展之间关系作初步的探讨。守恒是在物体外形发生变化时,仍能认识到该物体的某些特性并无改变的能力。守恒概念的形成与发展是瑞士心理学家皮亚杰(Piaget)一个很著名的发现。他通过大量的守恒实验来说明儿童认知发展的不同阶段。儿童在掌握守恒原则后,在认知发展上就达到一个新的阶段,即新的智力运算水平。Piaget 认为通常要到七岁左右。 | The Collaboration Croup for Research of Acquisition of the Concept of Conservation | 1985 | 心理科学通讯1985，8，6： | 3 |
| 3 | 深圳市华侨城生态广场景观设计显示文摘 | Aube Conception | 2006 | 风景园林2006，13，1： | 2 |
| 4 | Tourniquet painduring spinal anesthesia;a comparision of plain solutions of tetracine and bupivicaine显示文摘 | Conception MA Lamberh DH Welch KA | | 0，，09： | 1 |
| 5 | August18-19,2001显示文摘 | The ALARA(as low as reasonably achievable)concept in pediatric CT intelligent dose reduction:multidisciplinary conference organized by the Society of Pediatric Radiology | 2002 | Pediatr Radiol2002，32，： | 1 |
| 6 | Assisted following poor ovarian response to gonadotrophin stimulation 显示文摘 | Keay SD conception Liversedge NH Mathur RS | 1997 | Br J Obstet Gynaecol1997，104，5： | 1 |
| 7 | DEVS formalism: a framework for hierarchical model development 显示文摘 | Conception AI Ziegler P | 1998 | IEEE Trans Software Eng1998，14，2： | 1 |
| 8 | Experimental evaluation of axial trust in pumps 显示文摘 | Concept ETI Ine | 1999 | World pumps1999，，： | 1 |
| 9 | L'exemple du northern range 显示文摘 | Charlier J-Sur le concept de tonnages pondgrgs en ~conomie por- tuaire | 1994 | Cahiers Scientifiques du Transport1994，，29： | 1 |
| 10 | Peptide generation in the processing of dry - cured ham 显示文摘 | Eugenio Rodriguez Nunez Maria - Conception Aristoy and Fidel Toldra | 1995 | Food Chemistry1995，，53： | 1 |
| 11 | Report of the committee on basic auditing concepts显示文摘 | Auditing Concepts Committee | 1972 | The Accounting Review1972，，： | 1 |
| 12 | Comparisions in multidimensional separation显示文摘 | GIDDINGS J C CONCEPTS | 1987 | Journal of JHRC&CC1987，83，： | 1 |
| 13 | The Maastricht Consensus Report 显示文摘 | The European Helicobacter pylori Study Gurrent European concepts in the man- agement of Helicobacter pylori infection | 1997 | Gut1997，41，： | 1 |
| 14 | Evaluation of for wind power显示文摘 | Eriksson S Bernhoff H different turbine concepts Leijon M | 2008 | Re- newable and Sustainable Energy Reviews2008，12，5： | 1 |
| 15 | New Concepts for Assessment of Range and Condition显示文摘 | Task Group on Unity in Concepts and Terminology Committee Members | 1995 | Journal of Range Management1995，48，3： | 1 |
| 16 | Sweetman Bill显示文摘 | | 2002 | Jane''s Navy International2002，107，4： | 1 |
| 17 | Multidisciplinary conference organized by the Society of Pediatric Radiology显示文摘 | The ALARA (as low as reasonably achievable) concept in pediatric CT intelligent dose reduction | 2002 | Pediatr Radiol2002，32，： | 1 |
| 18 | s in pathophysiology and management 显示文摘 | Stasi R Evangelista ML Stipa E etldiopathic thrombocytopenic purpura:current concept al | 2008 | Thromb Haemost2008，99，1： | 1 |
| 19 | Vendee Concept Delta Calibra robot显示文摘 | Vendee Concept | 2012 | Poultry International2012，51，8： | 1 |
| 20 | Methods and applications in environmental model integration显示文摘 | ARGENT CONCEPTS R M | 2004 | Environmental Modelling & Software2004，19，： | 1 |
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