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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 | Improved response surface method for anti-slide reliability analysis of gravity dam based on weighted regression显示文摘The aim of this study was to design and construct an improved response surface method(RSM) based on weighted regression for the anti-slide reliability analysis of concrete gravity dam.The limitation and lacuna of the traditional RSM were briefly analyzed.Firstly,based on small experimental points,research was devoted to an improved RSM with singular value decomposition techniques.Then,the method was used on the basis of weighted regression and deviation coefficient correction to reduce iteration times and experimental points and improve the calculation method of checking point.Finally,a test example was given to verify this method.Compared with other conventional algorithms,this method has some strong advantages:this algorithm not only saves the arithmetic operations but also greatly enhances the calculation efficiency and the storage efficiency. | Jian-yun CHEN Qiang XY Jing LI Shu-li FAN Qiang xu | 2010 | Journal of Zhejiang University-Science A(Applied Physics & Engineering)2010，11，6： | 7 |
| 3 | Four-comer? arthrodesis? concentrator of nickel-titanium memory alloy for carpal collapse: a report on 18 cases显示文摘 | Xu YQ Qi BC Fan XY | 2012 | J Hand Surg Am2012，37，11： | 1 |
| 4 | Inhibition effect of secondal metabolites accumulated in a pervaporation membrane bioreactor on ethanol fermentation of Saccharomyces cerevisi, 显示文摘 | Fan SQ Xiao ZY Tang XY | 2014 | Bioresource Technology2014，162，： | 1 |
| 5 | Association between polymorphism of interleukin-17A and interleuki-17F genes and silicosis Susceptibility in Chinese Han People 显示文摘 | Chen Fan XY Jin YL | 2014 | Asian Pacific Journal of Cancer Prevention2014，15，20： | 1 |
| 6 | Significance of COX-1, COX-2 and iNOS expression in superficial gastritis, gastric mucosa atypical hyperplasia and gastric carcinoma显示文摘 | Luo YQ Wu KC Sun AH Pan BR Zhang XY Fan DM | 2000 | Chin J Digestion(中华消化杂志)2000，20，4： | 1 |
| 7 | Poly-L-Arginine Acts Synergistically with LPS to Promote the Release of IL-6 and IL-8 via p38/ERK Signaling Pathways in NCI-H292 Cells 显示文摘 | Fan XY Chen B Lu ZS | 2015 | Inflammation2015，，： | 1 |
| 8 | Association between RUNX3promoter methylation and gastric cancer: a meta-analysis显示文摘 | Fan XY Hu XL Han TM | 2011 | BMCGastroenterol2011，11，： | 1 |
| 9 | Progress in the treatment of chronicosteomyelitis 显示文摘 | Fan XH Liu XY Zhen P | 2002 | Zhongguo Gu Shang/China J Orthop Trauma2002，，： | 1 |
| 10 | Reversed expression of GRIM-1 and GRP78 in human non-small cell lung cancer显示文摘 | WU HM JIANG ZF FAN XY | 2014 | Hum Pathol2014，45，9： | 1 |
| 11 | Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium 显示文摘 | Zhang DS Fan GC Zhou XY | 2008 | Journal of Molecular and Cellular Cardiology2008，44，2： | 1 |
| 12 | Characterization of M2 antibodies in asymptomatic Chinese population 显示文摘 | JIANG XH ZHONG RQ FAN XY | 2003 | World J Gastroenterol2003，9，： | 1 |
| 13 | A novel differential expression system for gene modulation in Mycobacteria 显示文摘 | Fan XY Ma H Guo J | 2009 | Plasmid2009，61，1： | 1 |
| 14 | Rapid detection of rpoB gene muta- tions in rifampin-resistant Mycobacterium tuberculosis isolates in Shanghai by using the amplification refractory mutation system 显示文摘 | Fan XY Hu ZY Xu FH | 2003 | J Clin Microbiol2003，41，3： | 1 |
| 15 | Plant cyclopeptide RA-Ⅴ kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1-AKT interaction 显示文摘 | Fang XY Chen W Fan JT | 2013 | Toxicol Appl Pharmacol2013，267，1： | 1 |
| 16 | Extensive white matter abnormalities and clinical symptoms in drug-naive patients with first-episode schizophrenia a voxel-based diffusion tensor imaging study 显示文摘 | Zhang XY Fan FM Chen DC | 2016 | J Clin Psychiatry2016，77，2： | 1 |
| 17 | Pulmonary sclerosing hemangioma presenting with dense spindle stroma cells:a potential diagnostic pitfall显示文摘 | Lin XY Wang Y Fan CF | 2012 | Diagn Pathol2012，10，7： | 1 |
| 18 | Association between RUNX3promoter methylation and gastric cancer: a meta - analysis 显示文摘 | Fan XY Hu XL Han TM | 2011 | BMC Gastroenterol2011，25，11： | 1 |
| 19 | Differentiationof recurrent brain tumor versus radiation injury using diffu-sion tensor imaging in patients with new contrast-enhancinglesions显示文摘 | Sundgren PC Fan XY Weybright P | 2006 | Magn Reson Imaging2006，24，9： | 1 |
| 20 | A-type granite belts of two chemical sub-groups in central eastern China:Indication of ridge subduction显示文摘 | Li H Ling MX Li CY Zhang H Ding X Yang XY Fan WM Li YL and Sun WD | 2012 | Lithos2012，105，： | 1 |
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