RESUMO
UNLABELLED: The antiapoptotic protein Bcl-2 plays multiple roles in apoptosis, immunity, and autophagy. Its expression in tumors correlates with tumor grade and malignancy. The recapitulation 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.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neovascularização Patológica/fisiopatologia , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/fisiopatologia , Carcinoma Hepatocelular/secundário , Núcleo Celular/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Células Hep G2 , Humanos , Hipóxia/patologia , Hipóxia/fisiopatologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Nucleares/química , Proteínas Nucleares/genética , Estrutura Terciária de Proteína/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais/fisiologia , Proteína 1 Relacionada a Twist/química , Proteína 1 Relacionada a Twist/genéticaRESUMO
Inflammatory myofibroblastic tumor is a rare mesenchymal tumor, it can also be found on the trunk, head and neck, internal organs, and soft tissue. It has been named as inflammatory pseudotumor, plasma cell granuloma, solitary mast cell tumor, pseudotumor pneumonia and tissue cells, and other inflammatory pseudotumor. The main treatment of inflammatory myofibroblastic tumor patients is through surgical complete excision of the lesion.