Delogu, Salvatore (2011) L'Attivazione del fenotipo lipogenico è mediata dalla via di segnale AKT/mTOR ed associata alla prognosi del carcinoma epatocellulare umano. Doctoral Thesis.
Background and Aims: Mounting evidence supports an oncogenic role for de novo lipogenesis in cancer. Here, we define the importance of aberrant lipid biosynthesis in hepatocellular carcinoma (HCC). Methods: Expression of the main enzymes modulating lipogenesis was determined by real-time RT-PCR and immunoblotting in a collection of human HCC. Effects of the lipogenic enzymes on HCC growth were evaluated by inhibition and forced overexpression experiments in HCC cell lines. Pro-lipogenic role of the AKT protooncogene was assessed in vitro and in vivo. Results: In human liver specimens, a progressive induction of de novo lipogenesis occurred from non-tumorous surrounding livers to HCC. Extent of aberrant lipogenesis directly correlated with clinical aggressiveness, activation of the AKT/mTOR cascade, and suppression of AMPK proteins. In HCC cell lines, the AKT/mTORC1 pathway promoted activation of the lipogenic cascade via transcriptional and post-transcriptional mechanisms. Subsequent overexpression of AKT in the mouse liver triggered lipogenesis and tumor development. Suppression of ACLY, ACAC, FASN, or SCD1 lipogenic genes decreased proliferation and survival of HCC cell lines. Conclusions: Our results assign both a pathogenetic and prognostic significance to de novo lipogenesis in HCC. Moreover, the present findings open the possibility of inhibiting the lipogenic cascade and the AKT pathway as an innovative therapeutic approach for the treatment of human liver cancer.
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