@article{ec1eceae975a4230b1b8588758235c43,
title = "Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation",
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.",
keywords = "Cell cycle, Cyclin D1, ELF, Hepatocellular carcinoma, Transforming growth factor-β",
author = "K. Kitisin and N. Ganesan and Y. Tang and W. Jogunoori and Volpe, \{E. A.\} and Kim, \{S. S.\} and V. Katuri and B. Kallakury and M. Pishvaian and C. Albanese and J. Mendelson and M. Zasloff and A. Rashid and T. Fishbein and Evans, \{S. R.T.\} and A. Sidawy and Reddy, \{E. P.\} and B. Mishra and Johnson, \{L. B.\} and K. Shetty and L. Mishra",
note = "Funding Information: 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 Kiss A, Wang NJ, Xie JP, Thorgeirsson SS. (1997). Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 3: 1059–1066.",
year = "2007",
month = nov,
day = "1",
doi = "10.1038/sj.onc.1210513",
language = "English (US)",
volume = "26",
pages = "7103--7110",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Springer Nature",
number = "50",
}