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Cited by 219Multiple Myeloma Research and TreatmentsMicroRNA in disease regulationRNA Interference and Gene Delivery

Targeting miR-21 Inhibits In Vitro and In Vivo Multiple Myeloma Cell Growth

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Leone, Emanuela, Morelli, Eugenio, Di Martino, Maria T., Amodio, Nicola, Foresta, Umberto, Gullà, Annamaria, Rossi, Marco, Neri, Antonino +5 more·2013·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-12-3325PMC PMC4147955

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Abstract

Purpose: Deregulated expression of miRNAs plays a role in the pathogenesis and progression of multiple myeloma. Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of multiple myeloma. Experimental Design: Here, we investigated the in vitro and in vivo anti-multiple myeloma activity of miR-21 inhibitors. Results: Either transient-enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient multiple myeloma cells or interleukin-6–dependent/independent multiple myeloma cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of multiple myeloma cells, showing its tumor-promoting potential in multiple myeloma. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B, and BTG2), together with functional impairment of both AKT and extracellular signal–regulated kinase signaling, were achieved by transfection of miR-21 inhibitors into multiple myeloma cells. In vivo delivery of miR-21 inhibitors in severe combined immunodeficient mice bearing human multiple myeloma xenografts expressing miR-21induced significant antitumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors. Conclusion: Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-multiple myeloma activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease. Clin Cancer Res; 19(8); 2096–106. ©2013 AACR.

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  • Blocking miR-21 considerably reduced cell viability and prevented MM cells from growing clonogenically in stroma-free environments.

    “Furthermore, a different study showed that HMCLs had greater levels of mir-21 expression when attached to BMSCs and that blocking miR-21 considerably reduced cell viability and prevented MM cells from growing clonogenicly in stroma-free environments [170, 171].”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [170]

    Results §2 reports reduced survival after miR-21 inhibition in MM cell lines with high miR-21 expression, but not in lines with low expression (page unavailable). Results §3 reports a 75% reduction in U-266 colony formation in methylcellulose culture, not complete prevention of clonogenic growth; MM.1S clonogenicity was unaffected. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • According to Wang et al., miR-21 was expressed in MM cells that were attached to BMSCs and was also noticeably elevated in MM cells.

    “According to Wang et al., miR-21 was expressed in MM cells that were attached to BMSCs and was also noticeably elevated in MM cells.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [170]

  • Previous research indicates that MM-BMSCs exhibit higher expression levels of certain miRNAs, such as miR-223, miR-16, miR-519d, and miR-485-5p, than their normal counterparts.

    “Previous research indicates that MM-BMSCs exhibit higher expression levels of certain miRNAs, such as miR-223, miR-16, miR-519d, and miR-485-5p, than their normal counterparts [170] (Table 6).”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [170]

    Results §1 reports increased miR-21 in myeloma cells compared with normal plasma cells, and after myeloma cells adhere to bone marrow stromal cells. It does not report a comparison of miR-223, miR-16, miR-519d, or miR-485-5p expression in MM-BMSCs versus normal BMSCs; searches for those miRNAs and that stromal-cell comparison found no supporting passage. Page numbers were not provided in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Leone, E., Morelli, E., Di Martino, M. T., Amodio, N., Foresta, U., Gullà, A., Rossi, M., Neri, A., Giordano, A., Munshi, N. C., Anderson, K. C., Tagliaferri, P., & Tassone, P.
Affiliations
  • University of Siena (IT)
  • Authors' Affiliations: 1Medical Oncology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University and T. Campanella Cancer Center, Catanzaro; 2Department of Medical Sciences University of Milan, Hematology 1, IRCCS Policlinico Foundation, Milan; 3Human Pathology and Oncology Department, University of Siena, Siena, Italy; 4Department of Medical Oncology, Dana-Farber Cancer Institute; 5Boston Veterans Administration Healthcare System, West Roxbury, Boston, Massachusetts; and 6Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania
Corresponding author
Tassone, Pierfrancesco
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2013-04-15
Volume
19
Issue
8
Pages
2096-2106
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-12-3325
PMC
PMC4147955
OpenAlex
W2151371056
Cited by
219
References
0
Citations by year
2026: 4 · 2025: 10 · 2024: 14 · 2023: 15 · 2022: 15 · 2021: 25 · 2020: 21 · 2019: 14 · 2018: 19 · 2017: 14 · 2016: 19 · 2015: 20 · 2014: 21 · 2013: 8
FWCI
16.26
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Use Siena air (University of Siena) (submittedVersion, other-oa)
Funders
  • National Institutes of Health (5p01ca078378-15)
  • National Cancer Institute (P01-CA078378, P50CA100707, R01CA050947, P01CA155258)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
miR-21, multiple myeloma, miRNA inhibitors, PTEN, Akt signaling, ERK signaling, mesenchymal stem cells, interleukin-6, tumor growth inhibition, xenografts, cancer therapy, BTG2
MeSH terms
Animals, Cell Survival, Cells, Cultured, Humans, Male, Multiple Myeloma, Transfection, Tumor Cells, Cultured, Blotting, Western, Gene Expression Regulation, Neoplastic, RNA, Antisense, Mice, SCID, Immediate-Early Proteins, Reverse Transcriptase Polymerase Chain Reaction, rhoB GTP-Binding Protein, Xenograft Model Antitumor Assays, Tumor Suppressor Proteins, MicroRNAs, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice

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