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Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma

Cancer Gene Therapy volume 27, pages 869–877 (2020)Cite this article

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Abstract

Despite the fact that a few novel agents improve the outcome of patients, MM remains incurable. Hence, developing a novel treatment strategy may prove to be promising for the clinical management of MM. Noncoding small RNAs, a cluster of RNAs that do not encode functional proteins, have been underlined that play a pivotal role in the pathogenesis of MM. Our previous study indicated that miR-15a acted as a tumor suppressor, which inhibited the cell proliferation and promoted the apoptosis of MM cells. The level of miR-15a was downregulated in MM cells and correlated with inferior outcome of MM patients. In the present study, we first developed an oligo-single-stranded DNA mimicking the sequence of hsa-miR-15a-5p (OMM-15a) and modified with locked nucleic acid (LNA-15a) to evaluate its anti-MM effects. Our results indicated that the LNA-15a presented an exciting anti-MM effect that showed notable cell growth suppression and apoptosis promotion in MM and other cancer cell lines through downregulating the expression level of target genes BCL-2, VEGF-A, and PHF19. Moreover, LNA-15a treatment significantly improved the anti-MM activity of bortezomib with the synergism effect in OCI-My5 MM cells. In our in vivo study, LNA-15a treatment significantly suppressed the tumor growth, and prolonged the survival of mice compared with the control group. However, our results indicated that the native form of oligo-single-stranded DNA mimic of hsa-miR-15a-5p (OMM-15a) without any modification had no effective inhibition on cell growth, even after increasing the dosage of OMM-15a in the treatment. Altogether, our finding provides the preclinical rationale to support the oligo-single-stranded DNA mimic of hsa-miR-15a with LNA modification, which is a promising tool for the therapy of both MM and other tumors with miR-15a downregulation.

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Fig. 1: Structure of pre-miR-15a, OMM-15a, and LNA-15a.
Fig. 2: LNA-15a suppressed tumor cell growth and induced apoptosis.
Fig. 3: LNA-15a suppressed the target gene of hsa-miR-15a-5p.
Fig. 4: In vitro activity of LNA-15a combined with BTZ.
Fig. 5: The anti-MM activity of LNA-15a in vivo.

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Acknowledgements

We thank Lingling Cheng for helping in the in vivo study and Ning Ji for revising the paper.

Funding

This work was supported by the Natural Science Foundation of China (81570181 and 81400174 to MH and 81630007 to LQ); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences CAMS-2017-I2M-1-005, CAMS-2016-I2M-3-031, and CAMS-2017-I2M-1-015 (to MH and LQ); Tianjin Science and Technology Supporting Program (17JCYBJC27900 to MH), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018RC320012 to MH).

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Authors and Affiliations

  1. Guangxi Medical University, Nanning, 530021, China

    Zhongqing Li & Yongrong Lai

  2. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China

    Zhongqing Li, Lanting Liu, Chenxing Du, Zhen Yu, Yuanyuan Yang, Jie Xu, Xiaojing Wei, Lugui Qiu & Mu Hao

  3. Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

    Fenghuang Zhan

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Li, Z., Liu, L., Du, C. et al. Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma. Cancer Gene Ther 27, 869–877 (2020). https://doi.org/10.1038/s41417-020-0161-3

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