Skip to main content

Advertisement

SpringerLink
Log in

AM22, a novel synthetic microRNA, inhibits the proliferation of colorectal cancer cells by targeting core binding factor subunit β (CBFB)

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Our previous studies have revealed the important roles of the nonseed regions of microRNAs (miRNAs) in gene regulation, which provided novel insight into the development of miRNA analogs for cancer therapy. Here, we altered each nucleotide in the nonseed region of miR-34a and obtained novel synthetic miRNA analogs. Among them, AM22, with a base alteration from G to C at the 17th nucleotide of miR-34a, showed extensive antiproliferative activity against several colorectal tumor cell lines and achieved effective inhibition of core binding factor subunit β (CBFB) expression. Subsequent investigations demonstrated that AM22 directly targeted CBFB by binding to its 3'-untranslated region (3'-UTR). Inhibition of CBFB showed obvious antiproliferative activity on HCT-116 and SW620 cells. Furthermore, the antiproliferative effects of AM22 on these cells were also measured in xenograft mouse models. In conclusion, this study identified AM22 as a potential antitumor miRNA by targeting CBFB and provided a new design approach for miRNA-based cancer treatment by changing the nonseed region of miRNA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Sets of data or summaries generated during the present study are available from the corresponding author upon reasonable request.

References

  1. Dekker E, Rex D (2018) Advances in CRC Prevention: Screening and Surveillance. Gastroenterology 154(7):1970–1984

    Article  PubMed  Google Scholar 

  2. Troiani T, Napolitano S, Corte CD, Martini G, Martinelli E, Morgillo F, Ciardiello F (2016) Therapeutic value of EGFR inhibition in CRC and NSCLC: 15years of clinical evidence. Esmo Open 1: e000088

  3. Bartel D (2004) MicroRNAs Genomics, Biogenesis, Mechanism, and Function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  4. Esquela-Kerscher A, Slack F (2006) Oncomirs- microRNAs with a role in cancer. Nat Rev Cancer 6:259–269

    Article  CAS  PubMed  Google Scholar 

  5. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838. https://doi.org/10.1038/nature03702

    Article  CAS  PubMed  Google Scholar 

  6. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866. https://doi.org/10.1038/nrc1997

    Article  CAS  PubMed  Google Scholar 

  7. Eva S, Zoran C, Ján R, Karel S (2017) Alternative mechanisms of miR-34a regulation in cancer. Cell Death Dis 8: e3100

  8. Misso G, Martino MTD, Rosa GD et al. (2014) Mir-34: A New Weapon Against Cancer? Mol. Ther Nucleic Acids 3 9:e194

  9. Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H (2007) Differential Regulation of microRNAs by p53 Revealed by Massively Parallel Sequencing: miR-34a is a p53 Target That Induces Apoptosis and G1-arrest. Cell Cycle 6:1586–1593

    Article  CAS  PubMed  Google Scholar 

  10. Geng D, Song X, Ning F, Song Q, Yin H (2015) MiR-34a Inhibits Viability and Invasion of Human Papillomavirus-Positive Cervical Cancer Cells by Targeting E2F3 and Regulating Survivin. Int J Gynecol Cancer 25:707–713

    Article  PubMed  Google Scholar 

  11. Adams BD, Parsons C, Slack F (2016) The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas. Expert Opin Ther Targets 20:737–753

    Article  CAS  PubMed  Google Scholar 

  12. Mackiewicz M, Huppi K, Pitt JJ, Dorsey TH, Ambs S, Caplen NJ (2011) Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA. Breast Cancer Res Treat 130:663–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rokavec M, Öner MG, Li H et al (2014) IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Investig 124(4):1853–1867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gao J, Li N, Dong Y et al (2014) miR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer. Oncogene 34:4142–4152

    Article  PubMed  Google Scholar 

  15. Meng F, Chen Y, Yang M, Zhang H, Wang W (2021) Concomitant inhibition of B7–H3 and PD-L1 expression by a novel and synthetic microRNA delivers potent antitumor activities in colorectal tumor models. Invest New Drugs. https://doi.org/10.1007/s10637-021-01123-4

    Article  PubMed  Google Scholar 

  16. Lewis BP, Shih I, Jones-Rhoades M, Bartel D, Burge C (2003) Prediction of Mammalian MicroRNA Targets. Cell 115:787–798

    Article  CAS  PubMed  Google Scholar 

  17. Bader AG, Brown D, Winkler M (2010) The Promise of MicroRNA Replacement Therapy. Cancer Res 70:7027–7030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pipan V, Zorc M, Kunej T (2015) MicroRNA Polymorphisms in Cancer: A Literature Analysis. Cancers (Basel) 7:1806–1814

    Article  CAS  Google Scholar 

  19. Zhao D (2020) Single nucleotide alterations in MicroRNAs and human cancer-A not fully explored field. Non-coding RNA Research 5:27–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chipman LB, Pasquinelli AE (2019) miRNA Targeting: Growing beyond the Seed. Trends Genet 35(3):215–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sheu-Gruttadauria J, Xiao Y, Gebert LFR, MacRae I (2019) Beyond the seed: structural basis for supplementary microRNA targeting by human Argonaute2. EMBO J 13: e101153

  22. Broughton JP, Lovci MT, Huang JL, Yeo GW, Pasquinelli AE (2016) Pairing beyond the Seed Supports MicroRNA Targeting Specificity. Mol Cell 64:320–333. https://doi.org/10.1016/j.molcel.2016.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Thangavel G, Nayar S (2018) A Survey of MIKC Type MADS-Box Genes in Non-seed Plants: Algae, Bryophytes. Lycophytes and Ferns Front Plant Sci 9:510

    Article  PubMed  Google Scholar 

  24. Gang H, Shigesada K, Ito K, Wee HJ, Yokomizo T, Ito Y (2014) Dimerization with PEBP2β protects RUNX1/AML1 from ubiquitin–proteasome-mediated degradation. EMBO J 20:723–733

    Google Scholar 

  25. Malik N, Yan H, Moshkovich N et al (2019) The transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription. Nat Commun 10:2071. https://doi.org/10.1038/s41467-019-10102-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gonzales F, Barthélémy A, Peyrouze P, Fenwarth L, Preudhomme C, Duployez N, Cheok M (2021) Targeting RUNX1 in acute myeloid leukemia: preclinical innovations and therapeutic implications. Expert Opin Ther Targets 25:299–309

    Article  CAS  PubMed  Google Scholar 

  27. Lee-Thacker S, Choi Y, Taniuchi I, Takarada T, Yoneda Y, Ko C, Jo M (2018) Core Binding Factor 2 Expression in Ovarian Granulosa Cells Is Essential for Female Fertility. Endocrinology 159(5):2094–2109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Davis JN, Rogers D, Adams L et al (2010) Association of core-binding factor β with the malignant phenotype of prostate and ovarian cancer cells. J Cell Physiol 225: 875–887

  29. Sandberg K, Samson WK, Ji H (2013) Decoding noncoding RNA: the long and short of it. Circ Res 113:240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Acunzo M, Romano G, Nigita G et al (2017) Selective targeting of point-mutated KRAS through artificial microRNAs. Proc Natl Acad Sci USA 114:E4203–E4012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hong DS, Kang YK, Borad M et al (2020) Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. Br J Cancer 122:1630–1637. https://doi.org/10.1038/s41416-020-0802-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang X, Li J, Dong K et al (2015) Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal 27:443–452

    Article  CAS  PubMed  Google Scholar 

  33. Mohan M, Kumar V, Lackner A, Alvarez X (2015) Dysregulated miR-34a SIRT1 Acetyl p65 Axis Is a Potential Mediator of Immune Activation in the Colon during Chronic Simian Immunodeficiency Virus Infection of Rhesus Macaques. J Immunol 194:291–306

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This research was supported by the National Natural Science Foundation of China (No. 81773044), Social Development Project of Jiangsu Province (BE2019657), Qinglan Project of Jiangsu Province, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Author notes

  1. Fanyi Meng and Jiawei Li contributed equally to this work.

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Fanyi Meng, Jiawei Li, Haiyang Zhang, Hongjian Zhang & Weipeng Wang

  2. Institute of Systems Medicine, Peking Union Medical College Hospital (PUMCH), Suzhou, 215123, China

    Yajing Qiu

Authors
  1. Fanyi Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiawei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yajing Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haiyang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongjian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weipeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptulization: Meng and Wang. Study design and execution: Meng, Li and Qiu. Data analysis and summary: Meng and Li. Writing—original draft: Meng and Zhang. Writing—review & editing: Meng, Zhang and Wang.

Corresponding authors

Correspondence to Hongjian Zhang or Weipeng Wang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Research involving human participants and/or animals

Protocols for animal husbandry and experiments were approved by the Institutional Animal Care and Use Committee at Soochow University. All animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978).

Informed consent

Not applicable.

Consent for publication

All authors consented to publish this study in Investigational New Drugs.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 8777 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meng, F., Li, J., Qiu, Y. et al. AM22, a novel synthetic microRNA, inhibits the proliferation of colorectal cancer cells by targeting core binding factor subunit β (CBFB). Invest New Drugs 40, 469–477 (2022). https://doi.org/10.1007/s10637-021-01208-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-021-01208-0

Keywords

Search

Navigation