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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 | The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings显示文摘目的: 催乳激素家庭荷尔蒙包括生长荷尔蒙,胎盘的促黄体激素和催乳激素,它能调整 angiogenesis 经由没有并且前列腺素。然而,他们脉管的音调上的效果充分没被理解。这研究的目的是在老鼠上评估催乳激素家庭荷尔蒙的效果脉管的在 vitro 的音调。 | Carmen GONZALEZ Hector ROSAS-HERNANDEZ Brenda JURADO-MANZANO Manuel Alejandro RAMIREZ-LEE Samuel SALAZAR-GARClA Pedro Pablo MARTINEZ-CUEVAS Aida Jimena VELARDE-SALCEDO Humberto MORALES- LOREDO Ricardo ESPINOSA-TANGUMA Syed F ALl Rafael RUBIO | 2015 | Acta Pharmacologica Sinica2015，36，5： | 2 |
| 3 | The food and feeding habits of the silver pomfret,Pampus argenteus (Euphrasen),in Kuwait waters显示文摘 | Dadzie S Aboul S F All Q E | 2000 | Journal of Applied Ichthyology2000，16，2： | 1 |
| 4 | Effect of strain, type of natural antioxidant and sulphate ion on productive, physiological and hatching performance of native laying hens 显示文摘 | All M N Hassan M S Abd El-Ghany F A | 2007 | Int Poult Sci2007，6，： | 1 |
| 5 | Three natural zircon standards for U-Th-Pb, Lu-Hf, trace element and REE analyses显示文摘 | Wiedenbeck M Alle P Corfu F | 1995 | Creostan- dards Newsletter1995，19，1： | 1 |
| 6 | Building Effective Small - group Team Working Skill through Blended Learning at Malaysia Tertiary Institution 显示文摘 | All M F Joyes G Ellison L | 2014 | Procedia - Social and Behavioral Sciences2014，，： | 1 |
| 7 | Three Natural Zircon Standards for U-Th-Pb, Lu-Hf, Trace Element and REE Analyses 显示文摘 | Wiedenbeck M Alle P Corfu F | 1995 | Geostandards Newsletter1995，19，1： | 1 |
| 8 | Three-step approach to designing a metal-forming process显示文摘 | GUNASEKERA J S ALl A F | 1995 | JOM1995，47，6： | 1 |
| 9 | The strengths of cements reinforced with glass fiber显示文摘 | Grimer F J All M A | 1969 | Magazine of Concrete Research1969，21，66： | 1 |
| 10 | Minority charge separation in falling particles with bipolar charge显示文摘 | Bi F S All M A All R A | 1998 | Journal of Electrostatics1998，45，2： | 1 |
| 11 | Therapeutic po- tential of vasopressin receptor antagonists 显示文摘 | All F Guglin M Vaitkevicius P | 2007 | Drugs2007，67，6： | 1 |
| 12 | Heightened responses to stressors in patients with inflame matory bowel disease显示文摘 | ASHKAN F ALl K LOUIS D | 2005 | Am J Gastroenterol2005，100，8： | 1 |
| 13 | Three natural zircon standards for U-Th-Pb, Lu-Hf, trace element and REE analyses显示文摘 | Wiedenbeck M Alle P Corfu F | 1995 | Geostandards Newsletter1995，19，： | 1 |
| 14 | Structure represen-tation of asphahene GPC fractions derived from Kuwaiti re- sidual oils显示文摘 | ALl F A GHALOUM N HAUSER A | 2006 | Energy & Fuels2006，20，1： | 1 |
| 15 | A high performance and intrin- sically secure key establishment protocol for wireless sensor net- works显示文摘 | ALl F MEHDI B HOSSEIN S | 2011 | Computer Networks2011，55，8： | 1 |
| 16 | Pharmacokinetics and PK-PD model of danofloxacin in camel serum and tissue cage fluids 显示文摘 | Aliabadi F S All B I-I Landoni M F | 2003 | The Veterinary Journal2003，165，： | 1 |
| 17 | Three natural zircon standards for U-Th-Pb, Lu-Hfm trace element and REE analyses 显示文摘 | Widenbeck M Alle P Corfu F | 1995 | Geostandards and GeoanalyticalResearch1995，19，1： | 1 |
| 18 | Advantages ofusing subsurface flow constructed wetIands for wastewatertreatmentl in space applications:Ground-based mars base prototype显示文摘 | NELSON M ALLING A DEMPSTER W F | 2003 | Advances in Space Research2003，31，7： | 1 |
| 19 | Advantages of using subsurface flow constructed wetlands for wastewater treatment in space applications:Ground-based mars base prototype显示文摘 | NELSONN M ALLING A DEMPSTER W F | 2003 | Advances in Space Research2003，31，7： | 1 |
| 20 | Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium 显示文摘 | MITCHELL J A ALl F BAILEY L MORENO L | 2008 | Exp Physiol2008，93，1： | 1 |
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