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  • Original Article
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Role of anti-oncomirs miR-143 and -145 in human colorectal tumors

Abstract

We examined the expression levels of microRNAs (miRNAs (miRs)) in colorectal tumors (63 cancer specimens and 65 adenoma specimens) and paired non-tumorous tissues. Decreased expression of miR-143 and -145 was frequently observed in the adenomas and cancers tested, compared with miR-34a downregulation and miR-21 upregulation. Expression profiles of miR-143 and -145 were not associated with any clinical features. As the downregulation of miR-143 and -145 was observed even in the early phase of adenoma formation, the decreased expression of both miRs would appear to contribute mainly to the initiation step of tumorigenesis, not to the progression stage, and not to clinical prognostic factors. For clinical application, we changed the sequences of the passenger strand in the miR-143 duplex and performed chemical modification at the 3′-overhang portion of miR-143, leading to greater activity and stability to nuclease. The cell growth inhibitory effect of the chemically modified synthetic miR-143 in vitro was greater than that of endogenous miR-143. The miR-143 showed a significant tumor-suppressive effect on xenografted tumors of DLD-1 human colorectal cancer cells. These findings suggest that miR-143 and -145 are important onco-related genes for the initiation step of colorectal tumor development and that the chemically modified synthetic miR-143 may be a hopeful candidate as an RNA medicine for the treatment of colorectal tumors.

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References

  1. Kloosterman WP, Plasterk RH . The diverse functions of microRNAs in animal development and disease. Dev Cell 2006; 11: 441–450.

    Article  CAS  PubMed  Google Scholar 

  2. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101: 2999–3004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Croce CM, Calin GA . miRNAs, cancer, and stem cell division. Cell 2005; 122: 6–7.

    Article  CAS  PubMed  Google Scholar 

  4. Gregory RI, Shiekhattar R . MicroRNA biogenesis and cancer. Cancer Res 2005; 65: 3509–3512.

    Article  CAS  PubMed  Google Scholar 

  5. Eder M, Scherr M . MicroRNA and lung cancer. N Engl J Med 2005; 352: 2446–2448.

    Article  CAS  PubMed  Google Scholar 

  6. McManus MT . MicroRNAs and cancer. Semin Cancer Biol 2003; 13: 253–258.

    Article  CAS  PubMed  Google Scholar 

  7. Akao Y, Nakagawa Y, Naoe T . MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers. Oncol Rep 2006; 16: 845–850.

    CAS  PubMed  Google Scholar 

  8. Akao Y, Nakagawa Y, Naoe T . MicroRNA-143 and -145 in colon cancer. DNA Cell Biol 2007; 26: 311–320.

    Article  CAS  PubMed  Google Scholar 

  9. Takagi T, Iio A, Nakagawa Y, Naoe T, Tanigawa N, Akao Y . Decreased expression of microRNAs-143 and -145 in human gastric cancers. Oncology 2009; 77: 12–21.

    Article  CAS  PubMed  Google Scholar 

  10. Akao Y, Nakagawa Y, Kitade Y, Kinoshita T, Naoe T . Down-regulation of micoRNAs-143 and -145 in B-cell malignancies. Cancer Sci 2007; 98: 1914–1920.

    Article  CAS  PubMed  Google Scholar 

  11. Akao Y, Nakagawa Y, Iio A, Naoe T . Role of microRNA-143 in Fas-mediated apoptosis in human leukemia Jurkat cells. Leuk Res 2009; 33: 1530–1538.

    Article  CAS  PubMed  Google Scholar 

  12. Behlke MA . Progress towards in vivo use of siRNAs. Mol Ther 2006; 13: 644–670.

    Article  CAS  PubMed  Google Scholar 

  13. Ueno Y, Inoue T, Yoshida M, Yoshikawa K, Shibata A, Kitamura Y et al. Synthesis of nuclease-resistant siRNAs possessing benzen-phosphate backbones in their 3′-overhang regions. Bioor Med Chem Lett 2008; 18: 5194–5196.

    Article  CAS  Google Scholar 

  14. Ueno Y, Kato T, Sato K, Ito Y, Inoue T, Shibata A et al. Synthesis and properties of nucleic acid analogues consisting of a benzene-phosphate backbone. J Org Chem 2005; 70: 7925–7935.

    Article  CAS  PubMed  Google Scholar 

  15. Akao Y, Itoh T, Ohguchi K, Iinuma M, Nozawa Y . Interactive effects of polymethoxy flavones from Citrus on cell growth inhibition in human neuroblastoma SH-SY5Y cells. Bioorg Med Chem 2008; 16: 2803–2810.

    Article  CAS  PubMed  Google Scholar 

  16. Shin C . Cleavage of the star strand facilitates assembly of some microRNAs into Ago2-containing silencing complexes in mammals. Mol Cells 2008; 26: 308–313.

    CAS  PubMed  Google Scholar 

  17. Lingel A, Simon B, Izaurralde E, Sattler M . Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain. Nature 2003; 426: 465–469.

    Article  CAS  PubMed  Google Scholar 

  18. Yan KS, Yan S, Farooq A, Han A, Zeng L, Zhou MM . Structure and conserved RNA binding of the PAZ domain. Nature 2003; 426: 468–474.

    Article  PubMed  Google Scholar 

  19. Ma JB, Ye K, Patel DJ . Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain. Nature 2004; 428: 318–322.

    Article  Google Scholar 

  20. Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Yang GP, James RJ . Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 2003; 1: 882–891.

    CAS  PubMed  Google Scholar 

  21. Slaby O, Svoboda M, Fabian P, Smerdova T, Knoflickova D, Bednarikova M et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 2007; 72: 397–402.

    Article  CAS  PubMed  Google Scholar 

  22. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008; 299: 425–436.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV et al. MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 2004; 279: 52361–52365.

    Article  CAS  PubMed  Google Scholar 

  24. Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y et al. Role of miRNA-143 targeting KRAS in colorectal tumorigenesis. Oncogene 2009; 28: 1385–1392.

    Article  CAS  PubMed  Google Scholar 

  25. Schwarz DS, Hutvagner G, Du T, Xu Z, Aronin N, Zamore PD . Asymmetry in the assembly of the RNAi enzyme complex. Cell 2003; 115: 199–208.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Takagi, Dr Tanigawa (Osaka Medical College Hospital), Dr Takagi (Kyouritsu General Hospital), Dr Takahama, Dr Watanabe, Dr Iwata, Dr Kamiya, Dr Maruyama, Dr Shibata, Dr Kamano and Dr Ohkubo (Fujita Health University Hospital) for supplying samples. This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan.

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Correspondence to Y Akao.

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Akao, Y., Nakagawa, Y., Hirata, I. et al. Role of anti-oncomirs miR-143 and -145 in human colorectal tumors. Cancer Gene Ther 17, 398–408 (2010). https://doi.org/10.1038/cgt.2009.88

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