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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 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 |
| 3 | Chromium interlayers as a tool for enhancing diamond adhesion on copper 显示文摘 | ALl N AHMED W REGO C A FAN Q H | 2000 | Diamond and Related Materials2000，9，： | 1 |
| 4 | Response of two genetically diverse wheat cultivars to salt stress at differ- ent growth stages: leaf lipid peroxidation and phenolic contents 显示文摘 | ASHRAF M A ASHRAF M ALl Q | 2010 | Pak J Bot2010，42，1： | 1 |
| 5 | 5 - Aminolevolinic acid mitigates the cadmium- induced changes in Brassica napus as revealed by the biochemical and ultra - structural evaluation of roots 显示文摘 | All B Tao Q Zhou Y | 2013 | Eeotoxieol Environ Saf2013，1，92： | 1 |
| 6 | Cut-edge corrosion of a Zn-55Al-coated steel: A comparison between sulphate and chloride solutions 显示文摘 | VU A Q VUILLEMIN U OLTRA R ALLELY C | 2011 | Corrosion Science2011，53，： | 1 |
| 7 | High Na intake increases renal angiotensin lI levels and reduces expression of the ACE2-ATaR- MasR axis in obese Zueker rats显示文摘 | Samuel P All Q Sahuhi R | 2012 | Am J Physiol Renal Physiol2012，303，3： | 1 |
| 8 | Ion Transport in Four Canola Cuhivars as Influenced by Salt Stress显示文摘 | ALl Q ATHAR H U R ASHRAF M | 2006 | Pakistan Journal of Botany2006，38，5： | 1 |
| 9 | Isolation and identification of bo- vine Brucella isolates from Pakistan by biochemical tests and PCR 显示文摘 | All S Ali Q Melzer F | 2014 | Trop Anim Health Prod2014，46，1： | 1 |
| 10 | Expression of major HDL- associated antioxidant PON-1 is gender dependent and regulated during inflammation显示文摘 | bin All A Zhang Q Lim YK et hi | 2003 | Free Radic Biol Med2003，34，7： | 1 |
| 11 | Cardiac troponin I levels and alveolar - arterial Oxygen gradient in patients with community - acquired pneumonia 显示文摘 | MOAMMAR M Q ALl M I MAHMOOD N A | 2010 | Heart Lung Circ2010，19，2： | 1 |
| 12 | The food and feeding habitsof the silverpomfret,Pampus argenteus Euphrasen,in Kuwaitwaters显示文摘 | DADZIE S ABOUL S F ALL Q E | 2000 | Journal of Applied Ichthyology2000，16，2： | 1 |
| 13 | 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 |
| 14 | Cadmium: Toxicity and tolerance in plants显示文摘 | Hasan SA Fariduddin Q All B Hayat S Ahmad A | 2009 | Journal of Environmental Biology2009，30，： | 1 |
| 15 | 24-Epibrassinolide protects against the stress generated by salinity and nickel in Brassica juncea 显示文摘 | ALl B HAYAT S FARIDUDDIN Q | 2008 | Chemosphere2008，72，9： | 1 |
| 16 | 24-epibrassinolide protects against the stress generated by salinity and nickel in Brassica juncea 显示文摘 | ALl B HAYAT S FARIDUDDIN Q | 2008 | Chemosphere2008，72，： | 1 |
| 17 | Numerical study of wave barrier and its optimization design 显示文摘 | Bo Q All L lrini D M | 2014 | Finite Elements in Analysis and Design2014，84，： | 1 |
| 18 | A case of Gitelman syndrome with severe hyponatraemia and hypophosphataemia 显示文摘 | All A Masood Q Yaqub S | 2013 | Singaporc Med J2013，54，1： | 1 |
| 19 | Role of the angiolensin Ⅱ AT2 receptor in inflammation and oxidative stress: opposing effects in lean and obese Zucker rats显示文摘 | Sabuhi R All Q Asghar M | 2011 | Am J Physiol Renal Physiol2011，300，3： | 1 |
| 20 | DNA hypermethylation of the Forkhead box protein 3 ( FOXP3 ) tients with systemic sclerosis显示文摘 | Wang YY Wang Q Sun XH at all | 2014 | 47 promoter in CD4 T ceils of pa- Br J Dermatol2014，171，1： | 1 |
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