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Effect of Rapamycin on the Gene Expression Signature of Focal Lesions in a Model of Progenitor‐Derived HCC
Author(s) -
Adebayo Adeola,
FrancoisVaughan Heather,
Brilliant Kate,
Gruppuso Philip,
Sanders Jennifer
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.45.2
Subject(s) - laser capture microdissection , pi3k/akt/mtor pathway , biology , cancer research , transcriptome , rptor , ribosome biogenesis , carcinogenesis , cell growth , progenitor cell , rheb , mechanistic target of rapamycin , microbiology and biotechnology , gene expression , mtorc1 , gene , signal transduction , stem cell , genetics , rna , ribosome
Given that current treatment options for hepatocellular carcinoma (HCC) are of limited efficacy, we have focused on chemoprevention and the m echanistic T arget O f R apamycin (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 metabolism and ubiquitin‐mediated proteolysis. Ingenuity Pathway Analysis (IPA) was performed using input that consist of genes showing a 2.4 fold change and FDR<0.05. Results revealed several canonical pathways, including FXR/RXR function and activation, and upstream regulators, PPARA and HNF1A. These results indicate that inhibition of mTOR signaling early in the process of hepatic carcinogenesis has a persistent, anti‐growth effect associated with marked changes in gene expression.