Effect of Rapamycin on the Gene Expression Signature of Focal Lesions in a Model of Progenitor-Derived HCC

Given that current treatment options for hepatocellular carcinoma (HCC) are of limited efficacy, we have focused on chemoprevention and the mechanistic Target Of Rapamycin (mTOR), a nutrient-sensing serine/threonine protein kinase that regulates cell growth and metabolism. Using the Solt-Farber model of progenitor-derived HCC, we have shown that mTOR is activated in the early stages of preneoplastic foci development. Rapamycin, an mTOR inhibitor, blocks this activation. The aim of this study is to characterize the genetic signature and molecular pathogenesis of rapamycin-inhibited foci as compared to placebo progressive preneoplastic foci. Persistent foci, which were reduced by up to 80% in the rapamycin group, were isolated by laser capture microdissection and the transcriptome of the captured tissue analyzed by microarray. Gene Set Enrichment Analysis (GSEA) showed that rapamycin significantly (FDR<0.05) suppressed genes associated with ribosomal biogenesis, cell cycle progression, glutathione metabolis...