Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Upregulation of RECK gene expression by small double-stranded RNA targeting the promoter region

Cancer Gene Therapy volume 21, pages 164–170 (2014)Cite this article

Abstract

Recent studies have demonstrated that small double-stranded RNAs (dsRNAs) complementary to the promoter region of target genes enhance the expression of those genes following transfection into cells. Here we show that expression of the matrix metalloproteinase (MMP) inhibitor RECK is activated in the cultured tumor cell lines by transfection with dsRNA complementary to the promoter of the RECK gene, leading to suppression of the expression of MMPs and it inhibited tumor cell invasion. These results support the suggestion that dsRNA complementary to the promoter region of tumor suppressor genes would have potential as a novel antitumor agent.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Janowski BA, Huffman KE, Schwartz JC, Ram R, Hardy D, Shames DS et al. Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs. Nat Chem Biol 2005; 1: 216–222.

    Article  CAS  Google Scholar 

  2. Janowski BA, Huffman KE, Schwartz JC, Ram R, Nordsell R, Shames DS et al. Involvement of AGO1 and AGO2 in mammalian transcriptional silencing. Nat Struct Mol Biol 2006; 13: 787–792.

    Article  CAS  Google Scholar 

  3. Morris KV, Chan SW, Jacobsen SE, Looney DJ . Small interfering RNA-induced transcriptional gene silencing in human cells. Science 2004; 305: 1289–1292.

    Article  CAS  Google Scholar 

  4. Ting AH, Schuebel KE, Herman JG, Baylin SB . Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation. Nat Genet 2005; 37: 906–910.

    Article  CAS  Google Scholar 

  5. Mehndiratta M, Palanichamy JK, Pal A, Bhagat M, Singh A, Sinha S et al. CpG hypermethylation of the C-myc promoter by dsRNA results in growth suppression. Mol Pharm 2011; 8: 2302–2309.

    Article  CAS  Google Scholar 

  6. Hawkins PG, Santoso S, Adams C, Anest V, Morris KV . Promoter targeted small RNAs induce long-term transcriptional gene silencing in human cells. Nucleic Acids Res 2009; 37: 2984–2995.

    Article  CAS  Google Scholar 

  7. Janowski BA, Younger ST, Hardy DB, Ram R, Huffman KE, Corey DR . Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat Chem Biol 2007; 3: 166–173.

    Article  CAS  Google Scholar 

  8. Matsui M, Sakurai F, Elbashir S, Foster DJ, Manoharan M, Corey DR . Activation of LDL receptor expression by small RNAs complementary to a noncoding transcript that overlaps the LDLR promoter. Chem Biol 2010; 17: 1344–1355.

    Article  CAS  Google Scholar 

  9. Huang V, Place RF, Portnoy V, Wang J, Qi Z, Jia Z et al. Upregulation of Cyclin B1 by miRNA and its implications in cancer. Nucleic Acids Res 2012; 40: 1695–1707.

    Article  CAS  Google Scholar 

  10. Kosaka M, Kang MR, Yang G, Li LC . Targeted p21WAF1/CIP1 activation by RNAa inhibits hepatocellular carcinoma cells. Nucleic Acid Ther 2012; 22: 335–343.

    Article  CAS  Google Scholar 

  11. Hu J, Chen Z, Xia D, Wu J, Xu H, Ye ZQ . Promoter-associated small double-stranded RNA interacts with heterogeneous nuclear ribonucleoprotein A2/B1 to induce transcriptional activation. Biochem J 2012; 447: 407–416.

    Article  CAS  Google Scholar 

  12. Yang K, Shen J, Xie YQ, Lin YW, Qin J, Mao QQ et al. Promoter-targeted double-stranded small RNAs activate PAWR gene expression in human cancer cells. Int J Biochem Cell Biol 2013; 45: 1338–1346.

    Article  CAS  Google Scholar 

  13. Li LC, Okino ST, Zhao H, Pookot D, Place RF, Urakami S et al. Small dsRNAs induce transcriptional activation in human cells. Proc Natl Acad Sci USA 2006; 103: 17337–17342.

    Article  CAS  Google Scholar 

  14. Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara RM et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 2001; 107: 789–800.

    Article  CAS  Google Scholar 

  15. Takahashi C, Sheng Z, Horan TP, Kitayama H, Maki M, Hitomi K et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci USA 1998; 95: 13221–13226.

    Article  CAS  Google Scholar 

  16. Liu LT, Chang HC, Chiang LC, Hung WC . Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res 2003; 63: 3069–3072.

    CAS  PubMed  Google Scholar 

  17. Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A . Rational siRNA design for RNA interference. Nat Biotechnol 2004; 22: 326–330.

    Article  CAS  Google Scholar 

  18. Chu Y, Yue X, Younger ST, Janowski BA, Corey DR . Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter. Nucleic Acids Res 2010; 38: 7736–7748.

    Article  CAS  Google Scholar 

  19. Takagi S, Simizu S, Osada H . RECK negatively regulates matrix metalloproteinase-9 transcription. Cancer Res 2009; 69: 1502–1508.

    Article  CAS  Google Scholar 

  20. Huang V, Qin Y, Wang J, Wang X, Place RF, Lin G et al. RNAa is conserved in mammalian cells. PLoS One 2010; 5: e8848.

    Article  Google Scholar 

  21. Watts JK, Yu D, Charisse K, Montaillier C, Potier P, Manoharan M et al. Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs that are complementary to non-coding transcripts at gene promoters. Nucleic Acids Res 2010; 38: 5242–5259.

    Article  CAS  Google Scholar 

  22. Place RF, Wang J, Noonan EJ, Meyers R, Manoharan M, Charisse K et al. Formulation of small activating RNA into lipidoid nanoparticles inhibits xenograft prostate tumor growth by inducing p21 expression. Mol Ther Nucleic Acids 2012; 1: e15.

    Article  Google Scholar 

  23. Kang MR, Yang G, Place RF, Charisse K, Epstein-Barash H, Manoharan M et al. Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth. Cancer Res 2012; 72: 5069–5079.

    Article  CAS  Google Scholar 

  24. Chang HC, Cho CY, Hung WC . Downregulation of RECK by promoter methylation correlates with lymph node metastasis in non-small cell lung cancer. Cancer Sci 2007; 98: 169–173.

    Article  CAS  Google Scholar 

  25. Pesta M, Kulda V, Topolcan O, Safranek J, Vrzalova J, Cerny R et al. Significance of methylation status and the expression of RECK mRNA in lung tissue of patients with NSCLC. Anticancer Res 2009; 29: 4535–4539.

    CAS  PubMed  Google Scholar 

  26. Schwartz JC, Younger ST, Nguyen NB, Hardy DB, Monia BP, Corey DR et al. Antisense transcripts are targets for activating small RNAs. Nat Struct Mol Biol 2008; 15: 842–848.

    Article  CAS  Google Scholar 

  27. Morris KV, Santoso S, Turner AM, Pastori C, Hawkins PG . Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genet 2008; 4: e1000258.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by the Grant-in-Aid for challenging Exploratory Research from the Japan Society of Promotion of Sciences, grants from the Ministry of Health, Labor and Welfare of Japan, and a grant from Suzuken Memorial foundation (to FS).

Author information

Author notes

  1. F Sakurai and Y Nanjo: These authors equally contributed to this work.

Authors and Affiliations

  1. Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka Univeristy, Osaka, Japan

    F Sakurai, Y Nanjo, S Okamoto, M Tachibana & H Mizuguchi

  2. Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Unit, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    F Sakurai

  3. Laboratory of Hepatic Differentiation Research, National Institute of Biomedical Innovation, Osaka, Japan

    H Mizuguchi

  4. Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan

    H Mizuguchi

  5. Laboratory of iPS Research, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    H Mizuguchi

Authors
  1. F Sakurai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Nanjo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Tachibana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Mizuguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Sakurai.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sakurai, F., Nanjo, Y., Okamoto, S. et al. Upregulation of RECK gene expression by small double-stranded RNA targeting the promoter region. Cancer Gene Ther 21, 164–170 (2014). https://doi.org/10.1038/cgt.2014.12

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2014.12

This article is cited by

Search

Advanced search

Quick links