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Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3

World journal of Gastroenterology 2011年第34期17卷 3922-3932页

作者： 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. liver Cancer Institute Zhongshan Hospital and Shanghai Medical School Fudan University Shanghai 200032 China.

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 ***: 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 ***: 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.

关键词： Hepatocellular carcinoma Sorafenib Signal transducer and activator of transcription 3 Extracellular signal regulated kinase Akt

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