Genetic Alterations of the Siah-1 Gene in Hepatocellular Carcinomas

Aims: Siah-1 is the mammalian homolog of Drosophila seven in absentia (sina) and has been identified as a p53-inducible gene. Siah-1 can induce cell cycle arrests, tumor suppression, and apoptosis through a novel β-catenin degradation pathway. Methods: To determine whether genetic alterations of Siah-1 gene are involved in the development and/or progression of HCCs, we searched for mutation of the Siah-1 gene in 38 HCCs by single strand conformational polymorphism and sequencing. The effect of Siah-1 on β-catenin degradation was further examined in wild- and mutant- type Siah-1 transfected HEK 293T cells. Results: We found two frameshift mutations and one missense mutation of the Siah-1 gene. The cases with Siah-1 mutation showed nuclear translocation and cytoplasmic staining of β-catenin. Interestingly, three mutants of Siah-1 stabilized cytoplasmic levels of β -catenin, even after treatment of adriamycin. Furthermore, Three mutants failed to suppress cyclin D1 expression and to induce apoptosis. Conclusions: These data suggest that inactivating mutations of the Siah-1 may contribute to the development of HCCs through β-catenin stabilization and apoptosis block.