Roles Of STAT3 And SOCS3 In The Progression Of Human Hepatocelluar Carcinoma

BackgroundAltered expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and suppressor of cytokine signaling 3 (SOCS3) has been implicated in various human cancers. However, the clinical role of pSTAT3 and SOCS3 in hepatocellular carcinoma (HCC) is not well established.MethodsImmunohistochemical analysis of pSTAT3, SOCS3, Ki67 and VEGF expression was performed on tissue microarray from 138 HCC patients. The expression of STAT3 mRNA was further detected by in situ hybridization. The association of pSTAT3 and SOCS3 expression with clinicopathological factors and patient survival was analyzed.ResultsAltered expression of pSTAT3 and SOCS3 was observed in HCC specimens, compared to adjacent non-tumor tissue. Increased expression of pSTAT3 was correlated to large tumor size, higher clinical stage, Ki67 and VEGF expression, as well as patient poor survival. Decreased expression of SOCS3 was correlated the expression of Ki67, VEGF and pSTAT3, and patient poor survival. Moreover, the expression of pSTAT3 was conversely correlated to SOCS3 expression in HCC.ConclusionsOur results indicate that deregulated expression of pSTAT3 and SOCS3 might possess potential roles in the development and progression of HCC. PSTAT3 and SOCS3 should be further evaluated as a novel biomarker for HCC prognosis. Objective To investigate the roles of STAT3 and SOCS3 in the proliferation, migration and invasion of human hepatocellular carcinoma cell and the possible mechanism.Methods MTS method was used to detect the proliferation of HepG2 cells in three days after transfection with specific anti-STAT3 siRNA, anti-SOCS3 siRNA or negative control siRNA. The wound-healing assay was used to dectect the change of cell migration in the different cell manipulation groups. Cell migration and invasion assay was used to detect the change of cell migration and invasion in the different groups of siRNA and negative control by using Transwell chamber.Results Compared with the negative control groups, cell proliferation, migration and invasion of anti-STAT3 siRNA groups were significantly decreased (All P<0.01). On the contrary, cell proliferation, migration and invasion of the anti-SOCS3 siRNA group were significantly increased compared with the negative control group. Moreover, the expression of MMP-2, MMP-9 and c-myc was significantly altered in the anti-STAT3 or anti-SOCS3 siRNA group compared with negative control group.Conclusion Our data demonstrated STAT3 and SOCS3 play roles in the cell proliferation, invasion and migration through mediating the expression of MMP-2, MMP-9 and c-myc in vitro. Objective To investigate the effect of AG490 on the tumor growth, invasion and metastasis of hepatocellar cancer cells in nude mice in vivo and the possible mechanism.Methods We established the hepatocelluar cancer model in nude mice with HepG2 cells and gave the different groups of mice either the AG490 or Sodium Chloride by intraperitoneal injection. The tumor size in the mice was measured in the different time. The tumor weight and tumor inhibition rate were also evaluated. After 2 weeks treatment, all the nude mice were sacrificed, and the tumor and the lung of mice were observed by H-E staining. The expression of pSTAT3, SOCS3, Ki67, c-myc, MMP-2 and MMP-9 in tumor cells was detected by immunohistochemistry.Results Tumor volume in the AG490 group was smaller than the control group (P<0.01). After the treatment, significant difference was found in the tumor proliferation, local invasion and lung metastasis. The expression pSTAT3, Ki67, c-myc, MMP-2 and MMP-9, not SOCS3, in tumor cells of AG490 group was significantly decreased compared to them in the control group.Conclusion The AG490 could significantly inhibit the hepatocellar cancer cell growth, invasion and metastasis by blocking the STAT3 mediated pathway, suggesting STAT3 and SOCS3 play important roles in the development and progression of in HCC.