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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.

SIP1 is downregulated in hepatocellular carcinoma by promoter hypermethylation