Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation
Cell cycle; Cyclin D1; ELF; Hepatocellular carcinoma; Transforming growth factor-β
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. © 2007 Nature Publishing Group All rights reserved.
Kitisin, K., Ganesan, N., Tang, Y., Jogunoori, W., Volpe, E., Kim, S., Katuri, V., Kallakury, B., Pishvaian, M., Albanese, C., Mendelson, J., Zasloff, M., Rashid, A., Fishbein, T., Evans, S., Sidawy, A., Reddy, E., Mishra, B., Johnson, L., Shetty, K., & Mishra, L. (2007). Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation. Oncogene, 26 (50). http://dx.doi.org/10.1038/sj.onc.1210513