Abstract
Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta 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-beta 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Carcinoma, Hepatocellular / etiology*
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Carcinoma, Hepatocellular / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Line, Tumor
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Cyclin D
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Cyclins / antagonists & inhibitors
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Cyclins / metabolism*
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Humans
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Liver Neoplasms, Experimental / etiology*
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Liver Neoplasms, Experimental / metabolism
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Mice
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Mice, Knockout
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Microfilament Proteins / deficiency
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Microfilament Proteins / genetics
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Microfilament Proteins / physiology*
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Phosphorylation
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Receptors, Transforming Growth Factor beta / metabolism
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Retinoblastoma / metabolism
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Spectrin / deficiency
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Spectrin / genetics
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Spectrin / physiology*
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Transforming Growth Factor beta2 / antagonists & inhibitors*
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Transforming Growth Factor beta2 / metabolism
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Transforming Growth Factor beta2 / physiology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
Substances
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Carrier Proteins
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Cyclin D
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Cyclins
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Microfilament Proteins
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta2
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Tumor Suppressor Proteins
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fodrin
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Spectrin