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  • Original Article
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Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Oncogene volume 26, pages 7103–7110 (2007)Cite this article

Abstract

Transforming growth factor-β (TGF-β) signaling members, TGF-β receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf+/− mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-β signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

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Acknowledgements

We thank Tiffany Blake and Miguel Osandon for helping with clinical material, data, and specimen preparation and Dr Anita Roberts for providing the human TBRII plasmid. We greatly appreciate the support from Human Tissue Share Resource (HTSR), Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA. This work was supported by NIH grants RO1 CA106614A (LM), RO1 DK56111 (LM), R01 CA4285718A (LM), RO1 DK58637 (BM), VA Merit Award (LM) and R Robert and Sally D Funderburg Research Scholar (LM). EPR was supported by NIH grant P01CA095569.

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Authors and Affiliations

  1. Department of Surgical Sciences, School of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    K Kitisin, N Ganesan, Y Tang, W Jogunoori, E A Volpe, S S Kim, V Katuri, J Mendelson, M Zasloff, T Fishbein, S R T Evans, B Mishra, L B Johnson, K Shetty & L Mishra

  2. Department of Pathology, School of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    B Kallakury

  3. Department of Medical Oncology, School of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    M Pishvaian

  4. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    C Albanese

  5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Rashid

  6. Department of Veterans Affairs Medical Center, Washington, DC, USA

    A Sidawy & L Mishra

  7. Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA,

    E P Reddy

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Correspondence to L B Johnson, K Shetty or L Mishra.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kitisin, K., Ganesan, N., Tang, Y. et al. Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation. Oncogene 26, 7103–7110 (2007). https://doi.org/10.1038/sj.onc.1210513

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