Journal
CLINICAL CANCER RESEARCH
Volume 21, Issue 10, Pages 2399-2411Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-1437
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Funding
- Leukemia and Lymphoma Society of Canada
- Cancer Research Society
- national key lab for experimental hematology [zk-1102]
- Gan-Po 555 project, Jiangxi, China
- Nature Science Foundation of China [81172255]
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Purpose: Deregulation of miRNA has been implicated in the pathogenesis of multiple myeloma. We identified miR-137 and miR-197, mapped to the chromosome 1p (12)-(21) deletion region, and examined their antimyeloma activity as tumor suppressors. Experimental Design: The expression of miR-137/197 was examined in multiple myeloma and normal plasma cells by qRT-PCR. Functional effect of miR-137/197 was analyzed by cell viability, apoptosis, clonogenic, and migration assays. Antimyeloma activity of miR-137/197 was further evaluated in vivo by lentiviral-based or lipid-based delivery in a mouse xenograft model of multiple myeloma. Results: miR-137/197 expression was significantly lower in multiple myeloma cell lines and multiple myeloma patient samples compared with normal plasma cells. Transfection of miR-137/197 resulted in reduction of MCL-1 protein expression, as well as alteration of apoptosis-related genes, and induction of apoptosis, inhibition of viability, colony formation, and migration in multiple myeloma cells. MCL-1 was further validated as a direct target of miR-137/197. Conversely, overexpression of MCL-1 partially reverted the effect of miR-137/197. Importantly, in vivo lentiviral-mediated or intratumor delivery of miR-137/197 induced regression of tumors in murine xenograft models of multiple myeloma. Conclusions: Our study reveals a novel role of miR-137/197 as tumor suppressors in mediating apoptosis in multiple myeloma cells by targeting MCL-1. Our findings provide a proof-of-principle that lentivirus-based or formulated synthetic miR137/197 exerts therapeutic activity in preclinical models, and support a framework for development of miR-137/197-based treatment strategies in patients with multiple myeloma. (C) 2015 AACR.
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