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Updated: May 18, 2026
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells
Ze Tian1, Jian-jun Zhao, Yu-Tzu Tai
1LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
miRs play a critical role in tumor pathogenesis as either oncogenes or tumor-suppressor genes. However, the role of miRs and their regulation in response to proteasome inhibitors in multiple myeloma (MM) is unclear. In the current study, miR profiling in proteasome inhibitor MLN2238-treated MM.1S MM cells shows up-regulation of miR33b. Mechanistic studies indicate that the induction of miR33b is predominantly via transcriptional regulation. Examination of miR33b in patient MM cells showed a constitutively low expression. Overexpression of miR33b decreased MM cell viability, migration, colony formation, and increased apoptosis and sensitivity of MM cells to MLN2238 treatment. In addition, overexpression of miR33b or MLN2238 exposure negatively regulated oncogene PIM-1 and blocked PIM-1 wild-type, but not PIM-1 mutant, luciferase activity. Moreover, PIM-1 overexpression led to significant abrogation of miR33b- or MLN2238-induced cell death. SGI-1776, a biochemical inhibitor of PIM-1, triggered apoptosis in MM. Finally, overexpression of miR33b inhibited tumor growth and prolonged survival in both subcutaneous and disseminated human MM xenograft models. Our results show that miR33b is a tumor suppressor that plays a role during MLN2238-induced apoptotic signaling in MM cells, and these data provide the basis for novel therapeutic strategies targeting miR33b in MM.
Insights
MicroRNAs (miRs) are key in cancer. This study reveals miR33b acts as a tumor suppressor in multiple myeloma (MM), enhancing proteasome inhibitor therapy by targeting PIM-1.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- MicroRNAs (miRs) are crucial in tumor development, functioning as oncogenes or tumor suppressors.
- The specific roles and regulation of miRs in response to proteasome inhibitors in multiple myeloma (MM) remain largely unknown.
Purpose of the Study:
- To investigate the function and regulation of microRNAs in multiple myeloma (MM) cells treated with the proteasome inhibitor MLN2238.
- To elucidate the therapeutic potential of miR33b in MM, particularly in combination with proteasome inhibitor treatment.
Main Methods:
- Performed miR profiling on MLN2238-treated MM.1S MM cells to identify differentially expressed miRs.
- Conducted mechanistic studies to determine the transcriptional regulation of miR33b.
- Assessed the effects of miR33b overexpression on MM cell viability, migration, apoptosis, and sensitivity to MLN2238.
- Investigated the interaction between miR33b, PIM-1, and MLN2238 using luciferase assays and xenograft models.
Main Results:
- miR33b was significantly upregulated by MLN2238 treatment in MM cells, primarily through transcriptional regulation.
- Overexpression of miR33b reduced MM cell viability, migration, and colony formation, while increasing apoptosis and sensitivity to MLN2238.
- miR33b and MLN2238 negatively regulated the oncogene PIM-1; PIM-1 overexpression counteracted miR33b- and MLN2238-induced cell death.
- Overexpression of miR33b inhibited tumor growth and prolonged survival in MM xenograft models.
Conclusions:
- miR33b functions as a tumor suppressor in multiple myeloma (MM).
- miR33b plays a significant role in MLN2238-induced apoptotic signaling in MM cells.
- Targeting miR33b presents a promising therapeutic strategy for multiple myeloma (MM).
