Smad2 and Smad4 gene mutations in hepatocellular carcinoma

Yakıcıer, Mustafa Cengiz; Irmak, MB; Romano, A.; Kew, Michael C.; Öztürk, Mehmet

doi:10.1038/sj.onc.1202866

Cited by 149 publications

(90 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Also, in chronic hepatitis C infection, HCV-derived core protein associates with the Smad3 MH1 domain inhibiting its DNA-binding activity (Pavio et al, 2005). Smad2 and Smad4 gene mutations have also been identified in 5-10% HCCs (Yakicier et al, 1999;Longerich et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2007

View full text Add to dashboard Cite

Transforming growth factor-b (TGF-b) signaling members, TGF-b 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 þ /À 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 (Po0.017). 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-b 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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Smad2 mutations occur in 5% of HCCs (Yakicier et al, 1999;Longerich et al, 2004). Inhibitory Smad7 is upregulated in 60% of advanced HCCs (Park et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Somatic point mutations leading to amino-acid substitution in IGF2R or protein truncation were identified in 10-20% of the screened HCC in two series (De Souza et al, 1995;Oka et al, 2002). From another study (Yakicier et al, 1999), rare mutations leading to amino-acid substitutions were identified in MADH2/ Smad2 and MADH4/Smad4 genes (also known as DPC4 or deleted in pancreatic carcinoma 4). They mediate signaling by the TGF-b/activin/BMP-2/4 Genetics of hepatocellular tumors P Laurent-Puig and J Zucman-Rossi cytokine superfamily from receptor serine/threonine protein kinases at the cell surface to the nucleus (Lagna et al, 1996;Liu et al, 1996).…”

Section: )mentioning

confidence: 99%

Genetics of hepatocellular tumors

2006

View full text Add to dashboard Cite

Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1a (HNF1a) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/b-catenin pathway through CTNNB1/b-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently b-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.

show abstract

“…ductal pancreatic adenocarcinoma with Smad4 mutations in about 50%), seems to be intact in the vast majority of human HCCs. Smad2 mutations (o5%) and loss of Smad4 expression (10%) are infrequent molecular events (Yakicier et al, 1999;Longerich et al, 2004). Smad3 mutations have not been described in human hepatocarcinogenesis yet; however, recently published data clearly show a physical interaction between Smad3 and the HCV core protein, consequently antagonizing DNA-binding capacity of Smad3 and therefore reducing TGFb-dependent signaling (Cheng et al, 2004;Pavio et al, 2005).…”

Section: Transforming Growth Factor B Signaling Axismentioning

confidence: 99%