TGM2 inhibition attenuates ID1 expression in CD44-high glioma-initiating cells
Autor: | Ho Keung Ng, Aij Lie Kwan, Fu Rong Chen, Zhong Ping Chen, Qun Ying Yang, Ke Sai, Jesse Chung Sean Pang, Jun Fu |
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Rok vydání: | 2013 |
Předmět: |
Inhibitor of Differentiation Protein 1
Cancer Research Blotting Western Fluorescent Antibody Technique Mice Nude Apoptosis Biology Immunoenzyme Techniques Small hairpin RNA Mice chemistry.chemical_compound GTP-Binding Proteins Cancer stem cell Glioma Tumor Cells Cultured medicine Animals Humans Protein Glutamine gamma Glutamyltransferase 2 MTT assay RNA Small Interfering Cell Proliferation Transglutaminases Brain Neoplasms Cell Cycle Flow Cytometry medicine.disease Molecular biology Hyaluronan Receptors Oncology chemistry Terminal deoxynucleotidyl transferase Cell culture Basic and Translational Investigations Neoplastic Stem Cells Cancer research Neurology (clinical) Growth inhibition Stem cell |
Zdroj: | Neuro-Oncology. 15:1353-1365 |
ISSN: | 1523-5866 1522-8517 |
Popis: | CD44 is a molecular marker associated with cancer stem cell populations and treatment resistance in glioma. More effective therapies will result from approaches aimed at targeting glioma cells high in CD44.Glioma-initiating cell lines were derived from fresh surgical glioblastoma samples. Expression of tissue transglutaminase 2 (TGM2) was attenuated through lentivirus-mediated short hairpin RNA knockdown. MTT assay [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] was used to evaluate the growth inhibition induced by TGM2 inhibitor. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling was used to evaluate cell apoptosis following TGM2 inhibition. CD44(+) glioma stem cells were sorted by flow cytometry. A nude mice orthotopic xenograft model was used to evaluate the in vivo effect of TGM2 inhibitor.TGM2 was highly expressed in CD44-high glioblastoma tissues and tumor-derived glioma-initiating cell lines. TGM2 knockdown impaired cell proliferation and induced apoptosis in CD44-high glioma-initiating cell lines. Further studies indicated that expression of inhibitor of DNA binding 1 protein (ID1) is regulated by TGM2 and might be an important mediator for TGM2-regulated cell proliferation in CD44-high glioma-initiating cell lines. TGM2 inhibitor reduces ID1 expression, suppresses cell proliferation, and induces apoptosis in CD44-high glioma-initiating cell lines. Furthermore, TGM2 is highly expressed in CD44(+) glioma stem cells, while pharmacological inhibition of TGM2 activity preferentially eliminates CD44(+) glioma stem cells. Consistently, TGM2 inhibitor treatment reduced ID1 expression and induced apoptosis in our orthotopic mice xenograft model, which can be translated into prolonged median survival in tumor-bearing mice.TGM2 regulates ID1 expression in glioma-initiating cell lines high in CD44. Targeting TGM2 could be an effective strategy to treat gliomas with high CD44 expression. |
Databáze: | OpenAIRE |
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