Changes in bilirubin levels showed

a 10% improvement in the C/EBPα-saRNA group when compared to the control groups. Additionally, Selleckchem AZD0530 a 10% improvement in AST levels and 30% improvement in ALT levels were observed in the C/EBPα-saRNA-treated group when compared to the control groups. More significant was the reduction in tumor burden and the inhibition of preneoplastic lesions as detected by a 40% reduction in GST-p staining in the liver sections from the C/EBPα-saRNA-treated group. From a clinical perspective, this represents a very attractive therapeutic avenue since the expression level of C/EBPα in matched tumor tissues and nontumor tissues of HCC patients is down-regulated in the majority of tumor specimens. Moreover, patients with tumor samples showing higher levels of C/EBPα have a longer survival rate than those patients with tumor samples in which the expression of the C/EBPα is lower.[41] Our data support this evidence, suggesting

that up-regulation of C/EBPα provides a strong antiproliferative role in hepatocytes.[14, 42] To better understand the global molecular effect of C/EPBα-saRNA more specific to liver cancer, we performed a liver cancer pathway gene expression profile analysis. Such analysis of whole tumors is frequently confounded by the presence of cell types other than those with a transformed Liproxstatin-1 molecular weight phenotype.[43] Therefore, we profiled the gene expression changes brought about by C/EPBα-saRNA in HepG2 cells. The expression pattern of the liver cancer genes varied greatly between untransfected and C/EPBα-saRNA-transfected HepG2 cells. After normalization and cluster analysis, several important genes were significantly altered in expression. From the list of 20 genes that were up-regulated, 18 were known tumor suppressor genes. Of note was the up-regulation of RB, TP53, BID, and BAX to regulate cell cycle and apoptosis. The down-regulation of key genes were also noted, in particular ADAM17, a metalloproteinase reported as being a pathological feature of HCC.[44] ADAM17

is known to cause the shedding of receptor ligands such as epidermal TCL growth factor (EGF) and tumor necrosis factor alpha (TNFα),[45, 46] thus preventing regulation of key signaling events for normal cell signaling. Upon further analysis of the tumor suppressor genes, we noticed a pathway-defined trend where key effector genes of the tumor suppressors were down-regulated. Examples of this included repression of RHOA following up-regulation of the tumor suppressor DLC1, or up-regulation of RUNX3 to reverse expression of the oncogenes involved in EMT. Here we observed down-regulation of CTNB1 (β-catenin), HGF, SMAD7, and TGFB1. We also observed increased expression of the tumor suppressor SOC3, a known regulator of apoptosis and cell adhesion. Concomitantly, we also observed down-regulation of the associated SOC3 oncogenes including STAT3, cyclin-D1 (CCND1), XIAP, BIRC5, and MCL1.