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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 | Cloning and identification of an angiostatic molecule IP-10/crg-2显示文摘AIM To obtain human and murine cDNAsencoding IFN--y inducible protein 10 (lP--10) andcytokine responsive gene--2 (Crg-2).METHODS The encoding genes of lP-10 and Crg2 were amplified by RT--PCR from Cultured humanfibroblast cells and Balb/ c mouse liver treatedby IFN-y and TNF-a, respectively, and clonedinto plasmids of PUC19 and PGEM3Zf(+ ).RESULTS The nucleotide sequences ot theamplified DNA were confirmed by endonucleasesdigestion and sequencing.CONCLUSION Recombinant lP-10/ crg--2 geneclones with 306 hp and 314 hp inserts wereestablished for further research on biologicalactivities and ligands of hiP-10/mCrg--2. | Liu ZG Yang JH An HZ Wang HY He FT Han ZY Han Y Wu HP Xiao B Fan DM | 1999 | World Journal of Gastroenterology1999，5，3： | 2 |
| 3 | Mucosal immunization against, dental caries with plasmid DNA encoding pac gene of Streptococuus mutaru in rats显示文摘 | Jia R Guo JH Fan MW | 2004 | Vaccine2004，22，20： | 1 |
| 4 | A nation-wide multicenter 10-year (1999-2008) retrospective clinical epidemiological study of female breast cancer in China显示文摘 | Li J Zhang BN Fan JH | 2011 | BMC Cancer2011，11，： | 1 |
| 5 | Expression of αvβ6 integrin and collagen fibre in oral squamous cell carcinoma:association with clinical outcomes and prognostic implications显示文摘 | Li HX Zheng JH Fan HX | 2013 | J Oral Pathol Med2013，42，7： | 1 |
| 6 | Progression of carotid intima-media thickness and plasma antioxidants : The Los Angeles Atherosclerosis Study 显示文摘 | Dwyer JH Paul- Labrador M J Fan J | 2004 | Arteriosclerosis Thrombosis and Vascular Biology2004，24，2： | 1 |
| 7 | A nation-wide multicenter 10-year(1999-2008)retrospective clinical epidemiological study of femal breast cancer in China显示文摘 | Li J Zhang BN Fan JH | 2011 | BMC Cancer2011，11，： | 1 |
| 8 | Analysis of phenolic com- pounds in Epimedium plants using liquid chromatography coupled with electrospray ionization mass spectrometry显示文摘 | ZHAO HY SUN JH FAN MX | 2008 | Chromatogra- phyA2008，1190，12： | 1 |
| 9 | Cystatin C for glomeru-lar filtration rate estimation : coming of age 显示文摘 | Levey AS Fan L Eckfeldt JH | 2014 | Clin Chem2014，60，7： | 1 |
| 10 | A dosimetry study precisely outlining the heart substructure of left breast cancer patients u- sing intensity-modulated radiation therapy 显示文摘 | Fan LL Luo YK Xu JH | 2014 | J Appl Clin Med Phys2014，15，5： | 1 |
| 11 | A nation-wide multicenter 10- year (1999-2008) retrospective clinical epidemiologieal study of female breast caneer in China 显示文摘 | Li J Zhang BN Fan JH | 2011 | BMC Caneer2011，11，： | 1 |
| 12 | Colonization with arbuscular mycorrhizal fun- gus affects growth, drought tolerance and expression of stress-re- sponsive genes in Poncirus trifoliate 显示文摘 | Fan Q J Liu JH | 2011 | Acta Physiol Plant2011，33，4： | 1 |
| 13 | A nation-wide multicenter 10-year (1999-2008) retrospective clinical epidemiological study of female breast cancer in China显示文摘 | Li J Zhang BN Fan JH | 2011 | BMC Cancer2011，11，364： | 1 |
| 14 | Immunogenicity of CTLA4 fusion anti-caries DNA vaccine in rabbits and monkeys显示文摘 | Jia R Guo JH Fan MW | 2006 | Vaccine2006，24，24： | 1 |
| 15 | A study ofthe effect of plug-holing and boundary layer separationon natural ventilation with vertical shaft in urban roadtunnel fires 显示文摘 | Ji J Gao ZH Fan CG Zhong W Sun JH | 2012 | International Journal of Heat MassTransfer2012，21，21： | 1 |
| 16 | Experimentalstudy of air entrain ment mode with natural rentilation u-sing shafts in road tunnel fires 显示文摘 | Fan CG Ji J Gao ZH Han JY Sun JH | 2013 | International Journalof Heat and Mass Transfer2013，56，1： | 1 |
| 17 | A Nation-Wide multicenter 10- year ( 1999 -- 2008) retrospective clinical epidemiological study of female breast cancer in China显示文摘 | Li J Zhang BN Fan JH | 2011 | BMC Cancer2011，11，364： | 1 |
| 18 | Apoptotic and survivalsignals in hepatic stellate cells显示文摘 | Shen H Fan JH Minuk G | 2007 | Zhong Nan Da XueXue Bao Yi Xue Ban2007，32，5： | 1 |
| 19 | Effects of vertical shaftgeometry on natural ventilation in urban road tunnel fires显示文摘 | Ji J Fan CG Gao ZH Sun JH | | Journal of Civil Engineering and Management0，，： | 1 |
| 20 | Tanshinone IIA ameliorates seawater exposure-induced lung injury by inhibiting aquaporins (AQP) 1 and AQP5 expression in lung 显示文摘 | Li JH Xu M Fan OX | 2012 | Respir Physiol Neurobiol2012，181，1： | 1 |
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