Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma
| Autor: | Catrine Schulz, Dirk Geerts, Jasmine Kolb, Patrick N. Harter, Dorothea Schulte, Abdulghani Khilan, Jan Koster, S. Wehner, Thomas Klingebiel, Sebastian Czaplinski, Julian David Langer, Hermann Rohrer, Anja Groß |
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| Přispěvatelé: | AII - Cancer immunology, CCA - Cancer biology and immunology, Oncogenomics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biology, Hematology laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research Carcinogenesis Retinoic acid Mice Nude Tretinoin Biology medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound Mice Neuroblastoma Downregulation and upregulation Cell Line Tumor medicine Gene silencing Animals Humans Protein Isoforms Gene Silencing RNA Messenger Transcription factor neoplasms Cell Proliferation Homeodomain Proteins Cancer Cell Differentiation Exons medicine.disease Prognosis Alternative Splicing 030104 developmental biology Oncology chemistry Gene Knockdown Techniques Stage 4S Neuroblastoma Cancer research Transcription Factors |
| Zdroj: | Groß, A, Schulz, C, Kolb, J, Koster, J, Wehner, S, Czaplinski, S, Khilan, A, Rohrer, H, Harter, P N, Klingebiel, T, Langer, J D, Geerts, D & Schulte, D 2018, ' Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma ', Cancer Research, vol. 78, no. 8, pp. 1935-1947 . https://doi.org/10.1158/0008-5472.CAN-17-1860 Cancer research, 78(8), 1935-1947. American Association for Cancer Research Inc. Cancer Research, 78(8), 1935-1947. American Association for Cancer Research Inc. |
| ISSN: | 0008-5472 |
| DOI: | 10.1158/0008-5472.CAN-17-1860 |
| Popis: | Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy. Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935–47. ©2018 AACR. |
| Databáze: | OpenAIRE |
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