Basic—Liver, Pancreas, and Biliary TractIncreased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma
Section snippets
Human Tissue Samples
Eight normal livers, 68 HCCs and corresponding surrounding nontumor liver tissues were used. Tumors were divided in HCC with shorter/poor (HCCP; n = 36) and longer/better (HCCB; n = 32) survival, characterized by <3 and >3 years survival after partial liver resection, respectively.16 Patients' features are reported in Supplementary Table 1. Liver tissues were kindly provided by Dr Snorri S. Thorgeirsson (National Cancer Institute, Bethesda, MD) and collected at the Pietro Valdoni Surgery
Coordinated Activation of Lipogenic Proteins in Human HCC
Levels of the lipogenic pathway enzymes, including FASN, ACAC, ACLY, ME, SCD1, HMGCR, MVK, SQS, and those of their upstream inducers were investigated by immunoblotting and real-time reverse transcription PCR (Figure 1A–B, Supplementary Figure 1). No up-regulation of LXR-α was detected in non-neoplastic surrounding livers and HCC when compared with normal livers. A progressive induction of FASN, ACLY, ACAC, ME, SCD1, HMGCR, MVK, SQS, chREBP, LXR-β, SREBP1, and SREBP2 occurred in nontumorous
Discussion
In the present study, we show that aberrant activation of lipogenesis is a dominant oncogenic event in human HCC. Importantly, no significant differences were detected in the extent of de novo lipogenesis with regard to HCC etiology, suggesting that exacerbated lipogenesis is a general molecular phenomenon in hepatocarcinogenesis. Indeed, previous reports demonstrated that both hepatitis B and C viruses are able to induce FASN expression,23, 24, 25 and that overexpression of FASN is a typical
Acknowledgments
We thank Dr Mark Kay of Stanford University and Dr M. Celeste Simon of University of Pennsylvania for providing us with the constructs; and Sandra Huling of the UCSF Liver Center for histology support.
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by the Deutsche Forschungsgemeinschaft DFG (grant number Do622/2-1) to F.D.; National Institutes of Health grants R21CA131625 and R01CA136606 to X.C.; P30DK026743 for UCSF Liver Center. S.M. and G.D. were supported in part by a fellowship from the Master and Back Program, Sardegna Ricerche, RAS.