Loss of suppressors of cytokine signaling 3 promotes aggressiveness in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. Constitutive activation of STAT3 is found in various types of tumors, including HCC. In addition, suppressors of cytokine signaling 3 (SOCS3) signals for negative feedback to STATs, and is found to be inversely correlated with STAT3 expression. However, the exact role of SOCS3 in the tumorigenesis and progression of HCC is not fully understood. In this study we intended to show that SOCS3 inhibition promotes proliferation, migration, and invasion of HCC cells. HepG2, a human HCC cell line, was grown with SOCS3 siRNA or negative control (NC) transfection to assess the involvement of SOCS3 in cell proliferation, migration, and invasion by MTT, migration, and invasion assays, respectively. Western blot analysis was performed to examine the expression of STAT3, SOCS3, c-myc, matrix metalloproteinase (MMP)-2, and MMP-9 after transfection with either SOCS3 or NC siRNAs. A diethylnitrosamine (DEN)-induced HCC mouse model was assessed with or without injection of NSC 74859, a STAT3 inhibitor, to show accompanied changes among the expressions of STAT3, SOCS3, c-myc, MMP-2, and MMP-9. Inhibition of SOCS3 expression promoted the proliferation, migration, and invasion of HepG2 cells and increased the expression of c-myc, MMP-2, and MMP-9. HCC tumors developed in mice by DEN-induction with administration of NSC 74859 resulted in decreased expression of c-myc, MMP-2, and MMP-9, but not SOCS3. Loss of SOCS3 increased tumor growth, migration, and invasion and resulted in accompanied changes in expression of STAT3 and its target oncoproteins.
Department of General Surgery, First Affiliated Hospital of Anhui Medical University , Anhui, Hefei , P.R. China .
Wen-Yong
WY
Wu
Hyunchul
H
Kim
Chang-Le
CL
Zhang
Xiang-Ling
XL
Meng
Zheng-Sheng
ZS
Wu
D000636:Aminosalicylic Acids; D000818:Animals; D001557:Benzenesulfonates; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C520337:NSC 74859; D016271:Proto-Oncogene Proteins c-myc; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
SOCS3; STAT3; hepatocellular carcinoma