BIN1 tumor suppressor regulates Fas/Fas ligand–mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma
| Autor: | Huang Y, M W Su, Sharmin Esmailzadeh, Xiaoyan Jiang, Youwen Zhou |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Fas Ligand Protein Skin Neoplasms T cell Blotting Western CASP8 and FADD-Like Apoptosis Regulating Protein Fluorescent Antibody Technique Apoptosis Mice SCID Biology Real-Time Polymerase Chain Reaction Fas ligand Mice Mice Inbred NOD hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Humans RNA Messenger fas Receptor Adaptor Proteins Signal Transducing Cell Proliferation Gene knockdown Reverse Transcriptase Polymerase Chain Reaction Tumor Suppressor Proteins Cell Cycle Cutaneous T-cell lymphoma Nuclear Proteins Hematology Cell cycle Flow Cytometry Fas receptor medicine.disease Molecular biology Lymphoma T-Cell Cutaneous Haematopoiesis medicine.anatomical_structure Oncology Case-Control Studies Cancer research |
| Zdroj: | Leukemia. 29:1402-1413 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2015.9 |
| Popis: | The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4(+)CD7(-) Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL. |
| Databáze: | OpenAIRE |
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