Persistent effect of mTOR inhibition on preneoplastic foci progression and gene expression in a rat model of hepatocellular carcinoma

摘要: Hepatocellular carcinoma (HCC) is a heterogeneous disease in which tumor subtypes can be identified based on the presence of adult liver progenitor cells. Having previously mTOR pathway as critical to cell proliferation model injury, we investigated temporal activation signaling rat hepatic carcinogenesis. The employed chemical carcinogens and partial hepatectomy induce marker-positive HCC. Immunohistochemical staining for phosphorylated ribosomal protein S6 indicated robust complex 1 (mTORC1) activity early preneoplastic lesions that peaked during first week waned over subsequent 10 days. Continuous administration rapamycin by subcutaneous pellet 70 days markedly reduced development focal lesions, but resulted PI3K pathway. To test hypothesis mTORC1 was progression foci, limited 3-week period at start protocol. Focal lesion burden degree indistinguishable from seen with continuous administration. Short-term did not result or mTORC2 pathways. Microarray analysis revealed persistent effect short-term inhibition gene expression genetic signature reminiscent normal liver. We conclude stages carcinogenesis may due represent an effective chemopreventive strategy this form cancer.