Targeting of CD38 by the Tumor Suppressor miR-26a Serves as a Novel Potential Therapeutic Agent in Multiple Myeloma
| Autor: | Gabriel K. Habermehl, Huimin Liu, Xiaofeng Jiang, Fjorela Xhyliu, Jason Valent, Eric D. Hsi, Nikhil C. Munshi, Juraj Bodo, Wenjun Li, Jianhong Lin, Sarah L. Ondrejka, Kenneth C. Anderson, Geyou Ao, Yi Hu, Hayley Dysert, Benjamin E. Russell, Marcia Chappell, Jaroslaw P. Maciejewski, Chen Li, Qing Yi, Jianjun Zhao, Chuanfeng Fang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Antineoplastic Agents Apoptosis CD38 Article 03 medical and health sciences Mice 0302 clinical medicine Antineoplastic Agents Immunological immune system diseases Cell Movement hemic and lymphatic diseases Stable isotope labeling by amino acids in cell culture medicine Animals Humans Multiple myeloma Cell Proliferation biology Cell growth business.industry Daratumumab Antibodies Monoclonal medicine.disease ADP-ribosyl Cyclase 1 Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology medicine.anatomical_structure Oncology Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein Cancer research Heterografts Bone marrow Antibody business Multiple Myeloma |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 |
| Popis: | Multiple myeloma is an incurable refractory hematologic malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in multiple myeloma and tested single-wall carbon nanotube delivery of miR-26a in vitro and in vivo. miR-26a was downregulated in patients with multiple myeloma cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in multiple myeloma cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using stable isotope labeling by amino acids in cell culture (SILAC) medium, followed by mass spectrometry analysis. In multiple myeloma cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in multiple myeloma cells duplicated the multiple myeloma inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in multiple myeloma cells. In a human multiple myeloma xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for patients with multiple myeloma, but eventually resistance develops. In multiple myeloma cells, CD38 remained at low level during daratumumab treatment, but a high-quality response is sustained. In daratumumab-resistant multiple myeloma cells, CD38 expression was completely restored but failed to correlate with daratumumab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in multiple myeloma cells may have clinical benefit. Significance: These results highlight the tumor suppressor function of miR-26a via its targeting of CD38 and suggest the therapeutic potential of miR-26a in patients with multiple myeloma. |
| Databáze: | OpenAIRE |
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