Skip to main content

MicroRNAs as Therapeutic Targets and Colorectal Cancer Therapeutics

  • Chapter
  • First Online:
Non-coding RNAs in Colorectal Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 937))

Abstract

The diagnosis and treatment of colorectal cancer (CRC) have improved greatly over recent years; however, CRC is still one of the most common cancers and a major cause of cancer death worldwide. Several recently developed drugs and treatment strategies are currently in clinical trials; however, there is still a compelling need for novel, highly efficacious therapies. MicroRNAs (miRNAs) are short non-coding RNAs consisting of 20–25 nucleotides that regulate post-transcriptional gene expression by binding to the 3′-untranslated region of mRNAs. miRNAs are known to regulate cancer pathways and to be expressed aberrantly in cancer. Since their initial discovery, a large number of miRNAs have been identified as oncogenes, whereas others function as tumor suppressors. Furthermore, signaling pathways that are important in CRC (e.g. the WNT, MAPK, TGF-β, TP53 and PI3K pathways) are regulated by miRNAs. A single miRNA can simultaneously regulate several target genes and pathways, indicating the therapeutic potential of miRNAs in CRC. However, significant obstacles remain to be overcome, such as an efficient miRNA delivery system, and the assessment of safety and side effects. Thus, miRNA therapy is still developing and possesses great potential for the treatment of CRC. In this chapter, we focus on miRNAs related to CRC and summarize previous studies that emphasize the therapeutic aspects of miRNAs in CRC.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V, et al. Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids. 2014;3:e194.

    Article  CAS  PubMed  Google Scholar 

  2. Decuzzi P, Causa F, Ferrari M, Netti PA. The effective dispersion of nanovectors within the tumor microvasculature. Ann Biomed Eng. 2006;34:633–41.

    Article  CAS  PubMed  Google Scholar 

  3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    Article  CAS  PubMed  Google Scholar 

  4. Hermeking H. MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer. 2012;12:613–26.

    Article  CAS  PubMed  Google Scholar 

  5. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007;26:745–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124:1853–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nugent M, Miller N, Kerin MJ. Circulating miR-34a levels are reduced in colorectal cancer. J Surg Oncol. 2012;106:947–52.

    Article  CAS  PubMed  Google Scholar 

  8. Hahn S, Jackstadt R, Siemens H, Hunten S, Hermeking H. SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition. EMBO J. 2013;32:3079–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Neumuller RA, Knoblich JA. Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes Dev. 2009;23:2675–99.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sugiarto S, Persson AI, Munoz EG, Waldhuber M, Lamagna C, Andor N, et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell. 2011;20:328–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.

    Article  CAS  PubMed  Google Scholar 

  12. Bu P, Chen KY, Chen JH, Wang L, Walters J, Shin YJ, et al. A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell. 2013;12:602–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Valeri N, Braconi C, Gasparini P, Murgia C, Lampis A, Paulus-Hock V, et al. MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer. Cancer Cell. 2014;25:469–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nagel R, le Sage C, Diosdado Bvan der Waal M, Oude Vrielink JA, Bolijn A, et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res. 2008; 68:5795–802.

    Google Scholar 

  15. Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1:882–91.

    CAS  PubMed  Google Scholar 

  16. Drebber U, Lay M, Wedemeyer I, Vallbohmer D, Bollschweiler E, Brabender J, et al. Altered levels of the onco-microRNA 21 and the tumor-supressor microRNAs 143 and 145 in advanced rectal cancer indicate successful neoadjuvant chemoradiotherapy. Int J Oncol. 2011;39:409–15.

    PubMed  Google Scholar 

  17. Akao Y, Nakagawa Y, Hirata I, Iio A, Itoh T, Kojima K, et al. Role of anti-oncomirs miR-143 and -145 in human colorectal tumors. Cancer Gene Ther. 2010;17:398–408.

    Article  CAS  PubMed  Google Scholar 

  18. Schetter AJ, Okayama H, Harris CC. The role of microRNAs in colorectal cancer. Cancer J. 2012;18:244–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Strillacci A, Valerii MC, Sansone P, Caggiano C, Sgromo A, Vittori L, et al. Loss of miR-101 expression promotes Wnt/beta-catenin signalling pathway activation and malignancy in colon cancer cells. J Pathol. 2013;229:379–89.

    Article  CAS  PubMed  Google Scholar 

  20. Kanaan Z, Rai SN, Eichenberger MR, Roberts H, Keskey B, Pan J, et al. Plasma miR-21: a potential diagnostic marker of colorectal cancer. Ann Surg. 2012;256:544–51.

    Article  PubMed  Google Scholar 

  21. Pan X, Wang ZX, Wang R. MicroRNA-21. A novel therapeutic target in human cancer. Cancer Biol Ther. 2010;10:1224–32.

    Article  CAS  PubMed  Google Scholar 

  22. Xu F, Xu L, Wang M, An G, Feng G. The accuracy of circulating microRNA-21 in the diagnosis of colorectal cancer: a systematic review and meta-analysis. Color Dis. 2015;17:O100–7.

    Article  CAS  Google Scholar 

  23. Yamada A, Horimatsu T, Okugawa Y, Nishida N, Honjo H, Ida H, et al. Serum miR-21, miR-29a, and miR-125b are promising biomarkers for the early detection of colorectal neoplasia. Clin Cancer Res. 2015;21:4234–42.

    Article  CAS  PubMed  Google Scholar 

  24. Toiyama Y, Takahashi M, Hur K, Nagasaka T, Tanaka K, Inoue Y, et al. Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst. 2013;105:849–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27:2128–36.

    Article  CAS  PubMed  Google Scholar 

  26. Lin PL, Wu DW, Huang CC, He TY, Chou MC, Sheu GT, et al. MicroRNA-21 promotes tumour malignancy via increased nuclear translocation of beta-catenin and predicts poor outcome in APC-mutated but not in APC-wild-type colorectal cancer. Carcinogenesis. 2014;35:2175–82.

    Article  CAS  PubMed  Google Scholar 

  27. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci U S A. 2010;107:21098–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wagenaar TR, Zabludoff S, Ahn SM, Allerson C, Arlt H, Baffa R, et al. Anti-miR-21 suppresses hepatocellular carcinoma growth via broad transcriptional network deregulation. Mol Cancer Res. 2015;13:1009–21.

    Article  CAS  PubMed  Google Scholar 

  29. Huang L, Wang X, Wen C, Yang X, Song M, Chen J, et al. Hsa-miR-19a is associated with lymph metastasis and mediates the TNF-alpha induced epithelial-to-mesenchymal transition in colorectal cancer. Sci Rep. 2015;5:13350.

    Article  CAS  PubMed  Google Scholar 

  30. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–74.

    Article  CAS  PubMed  Google Scholar 

  31. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.

    Article  CAS  PubMed  Google Scholar 

  32. Schwartzberg LS, Rivera F, Karthaus MF, Asola G, Canon JL, Hecht JR, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:2240–7.

    Article  CAS  PubMed  Google Scholar 

  33. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26:13–21.

    Article  CAS  PubMed  Google Scholar 

  34. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120:635–47.

    Article  CAS  PubMed  Google Scholar 

  35. Ruzzo A, Graziano F, Vincenzi B, Canestrari E, Perrone G, Galluccio N, et al. High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease. Oncologist. 2012;17:823–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liao WT, Ye YP, Zhang NJ, Li TT, Wang SY, Cui YM, et al. MicroRNA-30b functions as a tumour suppressor in human colorectal cancer by targeting KRAS, PIK3CD and BCL2. J Pathol. 2014;232:415–27.

    Article  CAS  PubMed  Google Scholar 

  37. Guo C, Sah JF, Beard L, Willson JK, Markowitz SD, Guda K. The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer. 2008;47:939–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sheng L, He P, Yang X, Zhou M, Feng Q. miR-612 negatively regulates colorectal cancer growth and metastasis by targeting AKT2. Cell Death Dis. 2015;6:e1808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hiraki M, Nishimura J, Takahashi H, Wu X, Takahashi Y, Miyo M, et al. Concurrent targeting of KRAS and AKT by MiR-4689 is a novel treatment against mutant KRAS colorectal cancer. Mol Ther Nucleic Acids. 2015;4:e231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fang L, Li H, Wang L, Hu J, Jin T, Wang J, et al. MicroRNA-17-5p promotes chemotherapeutic drug resistance and tumour metastasis of colorectal cancer by repressing PTEN expression. Oncotarget. 2014;5:2974–87.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wu W, Yang J, Feng X, Wang H, Ye S, Yang P, et al. MicroRNA-32 (miR-32) regulates phosphatase and tensin homologue (PTEN) expression and promotes growth, migration, and invasion in colorectal carcinoma cells. Mol Cancer. 2013;12:30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zaravinos A. The regulatory role of MicroRNAs in EMT and cancer. J Oncol. 2015;2015:865816.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, et al. MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut. 2013;62:1315–26.

    Article  CAS  PubMed  Google Scholar 

  44. Bu P, Wang L, Chen KY, Rakhilin N, Sun J, Closa A, et al. miR-1269 promotes metastasis and forms a positive feedback loop with TGF-beta. Nat Commun. 2015;6:6879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang J, Du Y, Liu X, Cho WC, Yang Y. MicroRNAs as regulator of signaling networks in metastatic colon cancer. Biomed Res Int. 2015;2015:823620.

    PubMed  PubMed Central  Google Scholar 

  46. Yu Y, Kanwar SS, Patel BB, Oh PS, Nautiyal J, Sarkar FH, et al. MicroRNA-21 induces stemness by downregulating transforming growth factor beta receptor 2 (TGFbetaR2) in colon cancer cells. Carcinogenesis. 2012;33:68–76.

    Article  PubMed  Google Scholar 

  47. Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature. 2015;518(7537):107–10.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hirofumi Yamamoto .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Yamamoto, H., Mori, M. (2016). MicroRNAs as Therapeutic Targets and Colorectal Cancer Therapeutics. In: Slaby, O., Calin, G. (eds) Non-coding RNAs in Colorectal Cancer. Advances in Experimental Medicine and Biology, vol 937. Springer, Cham. https://doi.org/10.1007/978-3-319-42059-2_13

Download citation

Publish with us

Policies and ethics