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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 | Tumor size as a prognostic factor in patients with advanced gastric cancer in the lower third of the stomach显示文摘AIM: To explore the impact of tumor size on outcomes in patients with advanced gastric cancer in the lower third of the stomach. METHODS: We retrospectively analyzed the clinical records of 430 patients with advanced gastric cancer in the lower third of the stomach who underwent distal subtotal gastrectomy and D2 lymphadenectomy in our hospital from January 1998 to June 2004. Receiver-operating characteristic (ROC) curve analysis was used to determine the appropriate cutoff value for tumor size, which was measured as maximum tumor diameter. Based on this cutoff value, patients were divided into two groups: those with large-sized tumors (LSTs) and those with small-sized tumors (SSTs). The correlations between other clinicopathologic factors and tumor size were investigated, and the 5-year overall survival (OS) rate was compared between the two groups. Potential prognostic factors were evaluated by univariate KaplanMeier survival analysis and multivariate Cox's propor-tional hazard model analysis. The 5-year OS rates in the two groups were compared according to pT stage and pN stage. RESULTS: The 5-year OS rate in the 430 patients with advanced gastric cancer in the lower third of the stomach was 53.7%. The mean ± SD tumor size was 4.9 ± 1.9 cm, and the median tumor size was 5.0 cm. ROC analysis indicated that the sensitivity and specificity results for the appropriate tumor size cutoff value of 4.8 cm were 80.0% and 68.2%, respectively (AUC=0.795, 95%CI: 0.751-0.839, P=0.000). Using this cutoff value, 222 patients (51.6%) had LSTs (tumor size ≥ 4.8 cm) and 208 (48.4%) had SSTs (tumor size<4.8 cm). Tumor size was significantly correlated with histological type (P=0.039), Borrmann type (P=0.000), depth of tumor invasion (P=0.000), lymph node metastasis (P=0.000), tumor-nodes metastasis stage (P=0.000), mean number of metastatic lymph nodes (P=0.000) and metastatic lymph node ratio (P=0.000). Patients with LSTs had a significantly lower 5-year OS rate than those with SSTs (37.1% vs 63.3%, P=0.000). Univariate analysis showed that depth of tumor invasion (c 2=69.581, P=0.000), lymph node metastasis (c 2=138.815, P=0.000), tumor size (c 2=78.184, P=0.000) and metastatic lymph node ratio (c 2=139.034, P=0.000) were significantly associated with 5-year OS rate. Multivariate analysis revealed that depth of tumor invasion (P=0.000), lymph node metastasis (P=0.019) and tumor size (P=0.000) were independent prognostic factors. Gastric cancers were divided into 12 subgroups: pT2N0; pT2N1; pT2N2; pT2N3; pT3N0; pT3N1; pT3N2; pT3N3; pT4aN0; pT4aN1; pT4aN2; and pT4aN3. In patients with pT2-3N3 stage tumors and patients with pT4a stage tumors, 5-year OS rates were significantly lower for LSTs than for SSTs (P<0.05 each), but there were no significant differences in the 5-year OS rates in LST and SST patients with pT23N0-2 stage tumors (P > 0.05). CONCLUSION: Using a tumor size cutoff value of 4.8cm, tumor size is a prognostic factor in patients with pN3 stage or pT4a stage advanced gastric cancer located in the lower third of the stomach. | Hong-Mei Wang, Chang-Ming Huang, Chao-Hui Zheng, Ping Li, Jian-Wei Xie, Jia-Bin Wang, Jian-Xian Lin, Jun Lu, Department of Gastric Surgery, Affiliated Union Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, China Author contributions: Wang HM and Huang CM conceived of the study, analyzed the data, and drafted the manuscript Zheng CH, Li P and Xie JW helped revise the manuscript critically for important intellectual content Wang JB, Lin JX and Lu J helped collect data and design the study and all authors read and approved the final manuscript. | 2012 | World Journal of Gastroenterology2012，18，38： | 15 |
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