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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 | Interleukin-10 gene polymorphisms and hepatocellular carcinoma susceptibility:A meta-analysis显示文摘AIM: To assess the association between Interleu-kin-10 (IL-10) gene IL-10-1082 (G/A), IL-10-592(C/A), IL-10-819 (T/C) polymorphisms and hepatocellular carcinoma (HCC) susceptibility.METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% conf idence intervals (95% CIs) for IL-10 polymorphisms and HCC were cal-culated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS: This meta analysis included seven eligiblestudies, which included 1012 HCC cases and 2308 controls. Overall, IL-10-1082 G/A polymorphism was not associated with the risk of HCC (AA vs AG + GG, OR = 1.11, 95% CI = 0.90-1.37). When stratifying for ethnicity, the results were similar (Asian, OR = 1.12, 95% CI = 0.87-1.44; non-Asian, OR = 1.10, 95% CI = 0.75-1.60). In the overall analysis, the IL-10 polymorphism at position -592 (C/A) was identified as a genetic risk factor for HCC among Asians; patients carrying the IL-10-592*C allele had an increased risk of HCC (OR = 1.29, 95% CI = 1.12-1.49). No association was observed between the IL-10-819 T/C polymorphism and HCC susceptibility (TT vs TC + CC, OR = 1.02, 95% CI = 0.79-1.32).CONCLUSION: This meta-analysis suggests that IL-10-592 A/C polymorphism may be associated with HCC among Asians. IL-10-1082 G/A and IL-10-819 T/C polymorphisms were not detected to be related to the risk for HCC. | Yong-Gang Wei, Fei Liu, Bo Li, Xi Chen, Yu Ma, Lv-Nan Yan, Tian-Fu Wen, Ming-Qing Xu, Wen-Tao Wang, Jia-Yin YangYong-Gang Wei, Fei Liu, Bo Li, Xi Chen, Yu Ma, Lv-Nan Yan, Tian-Fu Wen, Ming-Qing Xu, Wen-Tao Wang, Jia-Yin Yang, Department of Liver and Vascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Prov- ince, China Author contributions: Wei YG and Liu F designed the study, collected and analyzed the data and wrote the manuscript Li B collected and analyzed the data and wrote the manuscript Chen X and Ma Y collected and analyzed the data Yan LN analyzed the data and contributed to the discussion Wen TF and Xu MQ revised the manuscript Wang WT and Yang JY contributed to the discussion Wei YG and Liu F contributed equally to this work. | 2011 | World Journal of Gastroenterology2011，17，34： | 3 |
| 3 | Haematological manifestations in patients with severe acute respiratory syndrome:retrospective analysis显示文摘 | Wong R S Wu A To K F | 2003 | BMJ2003，326，： | 2 |
| 4 | Increased ambulatory arterial stiffness index is associated with target organ damage in primary hypertension显示文摘 | LEONCINI G RAT TO E VIAZZI F | 2006 | Hypertension2006，48，： | 1 |
| 5 | Absence of the protease inhibitor cystatin C in inflammatory cells results in larger plaque area in plaque regression of apoE-deficient mice显示文摘 | Bengtsson E To F Grubb A | 2005 | Atherosclerosis2005，180，： | 1 |
| 6 | Influence of renal angiography in living potential kidney donors显示文摘 | Kjellevand TO Kolmannskog F Pfeffer P | 1991 | Acta Radiol1991，32，： | 1 |
| 7 | Absence of the protease inhibitor eystafin C in inflammatory cells results in largerplaque area in plaque regression of apoE - defieientmice 显示文摘 | Bengtssen E To F Gubb A | 2005 | Atheroselerosis2005，180，： | 1 |
| 8 | Evaluation of extraction methods from paraffin wax embedded tissues for PCR amplification of human and viral DNA显示文摘 | Chan P K Chan D P To K F | 2001 | J Clin Pathol2001，54，5： | 1 |
| 9 | Absence of the protease inhibi- tor cystatin C in inflammatory cells results in larger plaque area in plaque regression of apoE deficient mice 显示文摘 | Benglsson E To F Grubb A | 2005 | Atherosclerosis2005，180，1： | 1 |
| 10 | A microplasticity analysis of micro-cutting force variation in ultra-precision diamond turning 显示文摘 | LEE W B CHEUNG C F TO S | 2002 | Journal of Manufacturing Science and Engineering2002，124，： | 1 |
| 11 | Insights from the Randomized Aldactone E- valuation Study (RALES) 显示文摘 | Zannad F Alia F Dousset B et ah Limitation of excessive extracellular ma- trix turnover may contribute to survival benefit of spironolactone therapy in pa- tients with congestive heart failure | 2000 | Circulation2000，102，： | 1 |
| 12 | Lack of the eyste- ine protease inhibitor cystatin C promotes atherosclerosis in apolipoprotein E-deficient mice 显示文摘 | Bengtsson E To F Hakansson K | 2005 | Arterioscler Thromb Vase Biol2005，25，10： | 1 |
| 13 | Pathology of fatal human infection associated with avian influenza A HSN1 virus 显示文摘 | To K F Chan P K Chan K F | 2001 | J Med Virol2001，63，3： | 1 |
| 14 | Pathophysiologic changes in trauma patients and indications of damage control surgdery显示文摘 | Kegami K Yamada K Morim to F | 2002 | Nippon Gakkai Znsshi2002，103，7： | 1 |
| 15 | Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line 显示文摘 | To K F Chan M W Leung W K | 2004 | Br J Cancer2004，91，7： | 1 |
| 16 | Absence of the protease inhibitor Cystatin C in inflammatory cells results in larger plaque area in plaque regression of apoE - deficientmice显示文摘 | Bengtsson E To F Grubb A | 2005 | Atherosclerosis2005，180，1： | 1 |
| 17 | Pathology of human infection associated with avain influenza A H5 NI virus显示文摘 | To K F Chang P K Chan K F e tal | 2001 | J Med Virol2001，63，3： | 1 |
| 18 | Intravaseular Immune Surveillance by CXCR6 + NKT Cells Patrolling Liver Sinusoids显示文摘 | Geissmann F Cameron TO Sidobre S | 2005 | PLoS Biol2005，3，4： | 1 |
| 19 | Interspecies transmission and emergence of novel viruses:lessons from bats and birds显示文摘 | Chan J F To K K Tse H Jin D Y Yuen K Y | 2013 | Trends Microbiol2013，21，： | 1 |
| 20 | Mutations in corneal carbohydrate sulfotransferase 6 gene (CHST6) cause macular corneal dystrophy in Iceland显示文摘 | Liu NP Dew-Knight S Rayner M Jonasson F Akama TO Fukuda MN | 2000 | Mol Vis2000，6，： | 1 |
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