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      SIP1 is downregulated in hepatocellular carcinoma by promoter hypermethylation

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      Author
      Acun, T.
      Oztas, E.
      Yagci, T.
      Yakicier, M.C.
      Date
      2011
      Source Title
      BMC Cancer
      Print ISSN
      14712407
      Volume
      11
      Language
      English
      Type
      Article
      Item Usage Stats
      214
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      178
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      Abstract
      Background: Smad interacting protein-1 is a transcription factor that is implicated in transforming growth factor-β/bone morphogenetic protein signaling and a repressor of E-cadherin and human telomerase reverse transcriptase. It is also involved in epithelial-mesenchymal transition and tumorigenesis. However, genetic and epigenetic alterations of SIP1 have not been fully elucidated in cancers. In this study, we investigated mutations and promoter hypermethylation of the SIP1 gene in human hepatocellular carcinomas.Methods: SIP1 expression was analyzed in HCC cell lines and primary tumors in comparison to normal and non-tumor liver tissues by using semi-quantitative RT-PCR, quantitative real-time RT-PCR and immunohistochemistry. Mutation and deletion screening of the SIP1 gene were performed by direct sequencing in HCC-derived cells. Restoration of SIP1 expression was sought by treating HCC cell lines with the DNA methyl transferase inhibitor, 5-AzaC, and the histone deacetylase inhibitor, TSA. SIP1 promoter methylation was analyzed by the combined bisulfite restriction analysis assay in in silico-predicted putative promoter and CpG island regions.Results: We found that the expression of SIP1 was completely lost or reduced in five of 14 (36%) HCC cell lines and 17 of 23 (74%) primary HCC tumors. Immunohistochemical analysis confirmed that SIP1 mRNA downregulation was associated with decreased expression of the SIP1 protein in HCC tissues (82.8%). No somatic mutation was observed in SIP1 exons in any of the 14 HCC cell lines. Combined treatment with DNA methyl transferase and histone deacetylase inhibitors synergistically restored SIP1 expression in SIP1-negative cell lines. Analysis of three putative gene regulatory regions revealed tumor-specific methylation in more than half of the HCC cases.Conclusions: Epigenetic mechanisms contribute significantly to the downregulation of SIP1 expression in HCC. This finding adds a new level of complexity to the role of SIP1 in hepatocarcinogenesis. © 2011 Acun et al; licensee BioMed Central Ltd.
      Keywords
      azacitidine
      bisulfite
      DNA methyltransferase inhibitor
      histone deacetylase inhibitor
      messenger RNA
      Smad interacting protein 1
      transcription factor
      trichostatin A
      unclassified drug
      DNA methyltransferase
      histone deacetylase inhibitor
      homeodomain protein
      hydroxamic acid
      repressor protein
      trichostatin A
      ZEB2 protein, human
      article
      cancer cell culture
      cancer tissue
      computer model
      controlled study
      CpG island
      DNA methylation
      down regulation
      drug potentiation
      epigenetics
      exon
      gene deletion
      gene mutation
      gene sequence
      human
      human tissue
      immunohistochemistry
      liver
      liver carcinogenesis
      liver cell carcinoma
      major clinical study
      primary tumor
      promoter region
      protein expression
      restriction mapping
      reverse transcription polymerase chain reaction
      somatic mutation
      adult
      aged
      down regulation
      drug antagonism
      drug effect
      female
      gene expression regulation
      genetic transcription
      genetics
      liver cell carcinoma
      liver tumor
      male
      metabolism
      middle aged
      molecular genetics
      nucleotide sequence
      pathology
      promoter region
      tumor cell line
      Adult
      Aged
      Aged, 80 and over
      Azacitidine
      Base Sequence
      Carcinoma, Hepatocellular
      Cell Line, Tumor
      DNA Methylation
      DNA Modification Methylases
      DNA Mutational Analysis
      Down-Regulation
      Female
      Gene Expression Regulation, Neoplastic
      Histone Deacetylase Inhibitors
      Homeodomain Proteins
      Humans
      Hydroxamic Acids
      Liver Neoplasms
      Male
      Middle Aged
      Molecular Sequence Data
      Promoter Regions, Genetic
      Repressor Proteins
      Restriction Mapping
      Transcription, Genetic
      Young Adult
      Permalink
      http://hdl.handle.net/11693/21891
      Published Version (Please cite this version)
      http://dx.doi.org/10.1186/1471-2407-11-223
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