Its expression in tumors correlates with tumor grade and malignancy. The recapitulation Target Selective Inhibitor Library concentration of the normal developmental process of epithelial-mesenchymal transition (EMT) contributes to tumor cell plasticity. This process is also a characteristic of metastatic cells and vasculogenic mimicry. In the

present study we report functional and structural interactions between Bcl-2 and the EMT-regulating transcription factor Twist1 and the relationship with metastasis and vascular mimicry. Bcl-2 and Twist1 are coexpressed under hypoxia conditions. The Bcl-2 can bind to Twist1 in vivo and in vitro. This interaction involves basic helix-loop-helix DNA binding domain within Twist1 and through two separate domains within Bcl-2 protein. Formation of the Bcl-2/Twist1 complex facilitates the nuclear transport of Twist1 and leads to transcriptional activation of wide ranges of genes that can increase the tumor cell plasticity, metastasis, and vasculogenic mimicry. Finally, nuclear expression of Bcl-2 and Twist1 is correlated with poor survival of these patients in a cohort of 97 cases of human hepatocellular carcinoma. Conclusion: The results describe

a novel function of Bcl-2 in EMT induction, provide insight into tumor progression, and implicate the Bcl-2/Twist1 complex as a potential target for developing chemotherapeutics. (HEPATOLOGY 2011;) Bcl-2 is the founding member of a family of proteins that play important roles during development and disease. Bcl-2 family members exhibit either pro- or antiapoptotic behavior. They include six classical antiapoptotic proteins and three preapoptosis proteins that show canonical Bcl-2 homology Tanespimycin research buy domains (BH1-4). These domains interact to form functional hetero- or homodimers.1 Bcl-2

members interact to exert fine control over cell death. The classically defined interaction between Bcl-2 and Bax proteins at mitochondrial membrane voltage-dependent anion channels results in the release of Ca2+ and cytochrome C. Consequently, a cascade of cell death processes is initiated and leads to apoptosis and necrosis.2, 3 In addition, Bcl-2 family members also interact with other proteins to modify and regulate cellular metabolism, immune response, and autophagy.4-8 Taken together, these observations suggest that the Bcl-2 family operates by way Vildagliptin of diverse mechanisms to regulate cell growth and death. In many malignant tumors, Bcl-2 importantly localizes at the endoplasmic reticulum, nucleus, and other nonmitochondrial sites. The antiapoptotic action of Bcl-2 is also associated with poor prognosis.9, 10 Nevertheless, the functional link of Bcl-2 to the mechanisms of tumor progression remain unclear. Epithelial-mesenchymal transition (EMT) is a normal developmental process wherein phenotypic plasticity alters the properties of cell adhesion and migration. EMT has recently gained considerable attention as a mechanism leading to tumor metastasis.