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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 | Preparation of porous ceramic membrane from industrial product显示文摘BECAUSE ceramic membranes have excellent thermal stability,mechanic and structural stability,goodresistant stability to chemicals and microbes and high potential to be modified,on the one hand,ce-ramic membranes,as membrane separation materials,have an attractive prospect;on the other hand,it is possible to achieve the unification of reaction(especially for high temperature reaction)and sepa- | Li, AW Zhao, HB Gu, JH Ziong, GX | 1997 | Chinese Science Bulletin1997，42，9： | 5 |
| 3 | Comparative effects of recombinanthuman brain natriuretic peptide and dobutamine on acutedecompensated heart failure patients with different blood BNP levels显示文摘 | Pan HY Zhu JH Gu Y | 2014 | BMC Cardiovasc Disord2014，14，： | 1 |
| 4 | Neovascular potential of adiposederived stromal cells(ASCs)from diabetic patients显示文摘 | Gu JH Lee JS Kim DW | 2012 | Wound Repair Regen2012，20，2： | 1 |
| 5 | Activation of the inflammasome and enhanced migration of micropartiele-stimulated dendritic cells to the draining lymph node 显示文摘 | Meraz IM Melendez B Gu JH | 2012 | Mol Pharmaceut2012，9，7： | 1 |
| 6 | Single-stranded DNA aptamers specific for antibiotics tetracyclines显示文摘 | Niazi JH Lee SJ Gu MB | 2008 | Bioorg Med Chem2008，16，15： | 1 |
| 7 | Assessment of openversuslapa- roscopy - assisted gastrectomy in lymph node - pos - itive early gas- tric cancer: a retrospective cohort analysis 显示文摘 | An JY Heo GU Cheong JH | 2010 | J Surg Oneol2010，102，1： | 1 |
| 8 | Association between INS- VNTR polymorphism and polycystic ovary syndrome in a Korean population显示文摘 | Yun JH Gu BH Kang YB | 2012 | Gynecol Endocrinol2012，28，7： | 1 |
| 9 | Ultrasound biomicroscopy of anterior segment accommodative changes with posterior chamber phakic intraocular lens in high myopia显示文摘 | Du CX Wang JH Wang XY Dong Y Gu YS Shen Y | 2012 | Ophthalmology2012，119，1： | 1 |
| 10 | Radiation therapy of recurrent nasopharyngeal carcinoma-report on 219 patients 显示文摘 | Yan JH Hu YH Gu XZ | 1983 | Acta Radiol Oncol1983，22，1： | 1 |
| 11 | Spectrum of statin hepato- toxicity : experience of the drug-induced liver injury network 显示文摘 | Russo MW Hoofnagle JH Gu J | 2014 | Hepatology2014，60，2： | 1 |
| 12 | Gankyrin plays an essen- tial role in Ras-indaced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells显示文摘 | Man JH Liang B Gu YX | 2010 | J Clin Invest2010，120，8： | 1 |
| 13 | Effects of locking area on strength of 2-and 4-strand locking tendon repairs 显示文摘 | Xie RG Xue HG Gu JH | 2005 | J Hand Surg(Am)2005，30，3： | 1 |
| 14 | Interleukin-2 gene therapy of chronic neuropathic pain显示文摘 | Yao MZ Gu JF Wang JH | 2002 | Neuroscience2002，112，2： | 1 |
| 15 | Enzymatic resolution of diols derived from p-benzoquinones 显示文摘 | Jiangxin Gu Mary JH Carl RJ | 2001 | Tetrahedron Letters2001，42，： | 1 |
| 16 | Medial sural artery perforator flap for repair of the hand显示文摘 | Xie RG Gu JH Gong YP | 2007 | J Hand Surg Eur Vol2007，32，5： | 1 |
| 17 | Chronic cerebral hypoperfusion causes decrease of o-glcnacylation, hyperphosphorylation of tau and behav- ioral deficits in mice显示文摘 | Zhao Y Gu JH Dai CL | 2014 | Front Aging Neurosci2014，6，10： | 1 |
| 18 | Osteoprotegerin influences the bone resorption activity of osteoclasts显示文摘 | Fu YX Gu JH Zhang YR | 2013 | Int J Mol Med2013，6，： | 1 |
| 19 | Inhibition of NF-kappaB activation is associated with anti-inflammatory and anti-apoptotic effects of Ginkgolide B in a mouse model of cerebral ischemia/reperfusion injury 显示文摘 | Gu JH Ge JB Li M | 2012 | Eur J Pharm Sci2012，47，4： | 1 |
| 20 | Biodegradable luminescent porous silicon nanoparticles for in vivo applications显示文摘 | Park JH Gu L von Maltzahn G | 2009 | Nat Mater2009，8，4： | 1 |
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