Gastroenterology

Gastroenterology

Volume 140, Issue 3, March 2011, Pages 1071-1083.e5
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
Increased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma

https://doi.org/10.1053/j.gastro.2010.12.006Get rights and content

Background & Aims

De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC).

Methods

We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo.

Results

In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT−mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate−activated protein kinases. In HCC cell lines, the AKT−mammalian target of rapamycin complex 1−ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development.

Conclusions

De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.

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 1AB, 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.

References (32)

  • H.Q. Yin et al.

    Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice

    Toxicol Appl Pharmacol

    (2007)
  • M. Evert et al.

    Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

    Lab Invest

    (2005)
  • H.B. El-Serag et al.

    The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence

    Clin Gastroenterol Hepatol

    (2006)
  • S. Ladu et al.

    E2F1 inhibits c-Myc-driven apoptosis via PIK3CA/Akt/mTOR and COX-2 in a mouse model of human liver cancer

    Gastroenterology

    (2008)
  • S.S. Thorgeirsson et al.

    Molecular pathogenesis of human hepatocellular carcinoma

    Nat Genet

    (2002)
  • G.R. Hajer et al.

    Adipose tissue dysfunction in obesity, diabetes, and vascular diseases

    Eur Heart J

    (2008)
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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.

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