Persistent Effect of mTOR Inhibition on Preneoplastic Foci Progression and Gene Expression in a Rat Model of Hepatocellular Carcinoma

We previously identified the mTOR pathway as critical to progenitor cell proliferation in a model of liver injury, we investigated the temporal activation of mTOR signaling in a rat model of hepatic carcinogenesis. The model employed chemical carcinogens and partial hepatectomy to induce progenitor marker-positive HCC. Rats were administered the mTOR inhibitor rapamycin for a three week period and liver harvested one month following cessation of rapamycin treatment. Short-term rapamycin treatment resulted in a significant reduction of focal lesion burden. Microarray analysis was performed to characterize the gene expression signature of persistent focal lesions in the rapamcyin and placebo treated animals. This analysis revealed a persistent effect of short-term mTORC1 inhibition on gene expression that resulted in a genetic signature reminiscent of normal liver.