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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 | Expression of prokineticins and their receptors in the adult mouse brain显示文摘 | Cheng MY Leslie FM Zhou QY | 2006 | J Comp Neurol2006，498，6： | 1 |
| 3 | Less invasive sta- bilization system (LISS) versus proximal femoral nail anti- rotation (PFNA)in treating proximal femoral fractures : A prospective randomized study显示文摘 | Zhou FM Zhang ZSM Yang HM | 2012 | Journal of Orthopaedic Trauma2012，26，3： | 1 |
| 4 | Activation of serotonin receptors modulates synaptic transmission in rat cerebral cortex显示文摘 | Zhou FM Hablitz JJ | 1999 | J Neurophysiol1999，82，： | 1 |
| 5 | Signaling through Rho GTPase pathway as viable drug target 显示文摘 | Lu Q Longo FM Zhou H | 2009 | Curr Med Chem2009，16，11： | 1 |
| 6 | Less invasive stabilizationsystem(LISS)versus proximal femoral nail antirotation (PFNA)in treating proximal femoral fractures : Aprospective randomizedstudy显示文摘 | Zhou FM Zhang ZSM Yang HM | 2012 | J ournal of Orthopaedic Trauma2012，26，3： | 1 |
| 7 | Draft genome of the kiwifruit Actinidia chinensis 显示文摘 | Huang SX Ding J Deng DJ Tang W Sun HH Liu DY Zhang L Niu XL Zhang X Meng M Yu JD Liu J Han Y Shi W Zhang DF Cao SQ Wei ZJ Cui YL Xia YH Zeng HP Bao K Lin L Min Y Zhang H Miao M Tang XF Zhu YZ Sui Y Li GW Sun HJ Yue JY Sun JQ Liu FF Zhou LQ Lei L Zheng XQ Liu M Huang L Song J Xu CH Li JW Ye KY Zhong SL Lu BR He GH Xiao FM Wang HL Zheng HK Fei ZJ Liu YS | 2013 | Nat Commun2013，4，： | 1 |
| 8 | 'Cocktail' approaches and strategies in drug development:valuable tool or flawed science显示文摘 | Zhou HH Zeen T James FM | 2004 | J Clin Pharmacol2004，44，： | 1 |
| 9 | High-resolution analyses of human leukocyte antigens allele and haplotype frequencies based on 169995 volunteers from the China bone marrow donor registry program显示文摘 | Zhou XY Zhu FM Li JP | 2015 | PLoS One2015，10，01： | 1 |
| 10 | The mtDNA control region structure and preliminary phylogenetic relationships of the genus Gampsocleis (Orthoptera:Tettigoniidae)显示文摘 | Zhang YX Zhou ZJ Chang YL Yang MR Shi FM | | 0，，： | 1 |
| 11 | How double ridges and furrows mulched with plastic film affect soil water,soil temperature and yield of maize on the semiarid Loess Plateau of China显示文摘 | Zhou LM Li FM Jin SL | 2009 | Field Crops Research2009，113，1： | 1 |
| 12 | The mitochondrial genome of Ruspolia dubia (Orthoptera:Conocephalidae) contains a short A +T-rich region of 70 bp in length显示文摘 | Zhou ZJ Huang Y Shi FM | | 0，，09： | 1 |
| 13 | Effects of DIMBOA on impulse discharges of maxillary lateral sensillum styloconicum of armyworm larvae显示文摘THE DIMBOA (2, 4-dihydroxy-7-methoxy-1, 4-benzoxazin-3-one), a secondary product present in corn plants, plays an important role in protecting the plant against the pest attack. DIMBOA is rich in seedlings of cereal crops, especially in maize. Many investigators demonstrated a linear relationship between the DIMBOA content in plant and the resistance of the plant to pest. Feng et al. (1992) summarized that the toxicity of DIMBOA is associated | Yang, DM Luo, L Yan, FM Cheng, HW Zhou, PA | 1997 | Chinese Science Bulletin1997，42，1： | 1 |
| 14 | How double ridges and furrows mulched with plastic film affect soil water,soil temperature and yield of maize on the semiarid Loess Plateau of China显示文摘 | Zhou LM Li FM Jin SL | 2009 | Field Crops Research2009，113，： | 1 |
| 15 | Synaptic plasticity and nicotine addiction显示文摘 | Dani JA Ji D Zhou FM | 2001 | Neuron2001，31，： | 1 |
| 16 | p38 Mitogen-activated protein kinase and alkaline phosphatase in human dental pulp cells显示文摘 | Wang FM Hu T Zhou X | | 0，，1： | 1 |
| 17 | Synaptic plasticity and nicotine addiction显示文摘 | Dani JA Ji D Zhou FM | 2001 | Neuron2001，31，3： | 1 |
| 18 | Signaling through Rho GTPase pathway as viable drug target 显示文摘 | Lu Q Longo FM Zhou H | 2009 | Curr Med Chem2009，16，11： | 1 |
| 19 | Economic evalua- tions of angiotensin-converting enzyme inhibitors and angiotensin II re- ceptor blockers in type 2 diabetic nephropathy:a systematic review 显示文摘 | Huang Y Zhou Q Haaijer-Ruskamp FM | 2014 | BMC Nephrol2014，15，1： | 1 |
| 20 | Signaling through Rho GTPase pathway as viable drug target 显示文摘 | Lu Q Longo FM Zhou H Massa SM Chen YH | 2009 | Curt Med C''hem2009，16，11： | 1 |
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