1. ¹Department of Surgical Sciences, School of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
2. ²Department of Pathology, School of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
3. ³Department of Medical Oncology, School of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
4. ⁴Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
5. ⁵Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6. ⁶Department of Veterans Affairs Medical Center, Washington, DC, USA
7. ⁷Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA

Correspondence: Dr L Mishra, Department of Surgery, Georgetown University, Med/Dent Bldg., Room# NW 207-213, 3900 Reservoir Rd., NW, Washington, DC 20007, USA. E-mail: lm229@georgetown.edu, lopamishra@yahoo.com; Dr K Shetty or Dr LB Johnson, Georgetown University Hospital, 2 Main Building, Transplant Institute, 3900 Reservoir Rd., NW, Washington, DC 20007, USA. E-mails: kirti.shetty@medstar.net or lynt.johnson@medstar.net

Received 20 December 2006; Revised 26 March 2007; Accepted 4 April 2007; Published online 4 June 2007.

Abstract

Transforming growth factor- (TGF-) signaling members, TGF- 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- 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.