Tumor Biology

, Volume 36, Issue 3, pp 1701–1710 | Cite as

MicroRNA-93 suppress colorectal cancer development via Wnt/β-catenin pathway downregulating

  • Qingchao Tang
  • Zhaoxia Zou
  • Chendan Zou
  • Qian Zhang
  • Rui Huang
  • Xu Guan
  • Qiang Li
  • Zhongjing Han
  • Dayong Wang
  • Huiyan Wei
  • Xu Gao
  • Xishan Wang
Research Article


MicroRNA-93 (miR-93) is involved in several carcinoma progressions. It has been reported that miR-93 acts as a promoter or suppressor in different tumors. However, till now, the role of miR-93 in colon cancer is unclear. Herein, we have found that expression of miR-93 was lower in human colon cancer tissue and colorectal carcinoma cell lines compared with normal colon mucosa. Forced expression of miR-93 in colon cancer cells inhibits colon cancer invasion, migration, and proliferation. Furthermore, miR-93 may downregulate the Wnt/β-catenin pathway, which was confirmed by measuring the expression level of the β-catenin, axin, c-Myc, and cyclin-D1 in this pathway. Mothers against decapentaplegic homolog 7 (Smad7), as an essential molecular protein for nuclear accumulation of β-catenin in the canonical Wnt signaling pathway, is predicted as a putative target gene of miR-93 by the silico method and demonstrated that it may be suppressed by targeting its 3′UTR. These findings showed that miR-93 suppresses colorectal cancer development via downregulating Wnt/β-catenin, at least in part, by targeting Smad7. This study revealed that miR-93 is an important negative regulator in colon cancer and suggested that miR-93 may serve as a novel therapeutic agent that offers benefits for colon cancer treatment.


Colorectal cancer MicroRNA-93 Wnt/β-catenin Invasion Proliferation 



The work was supported by the National Natural Science Foundation of China (81272706).

Conflicts of interest


Supplementary material

13277_2014_2771_MOESM1_ESM.doc (118 kb)
ESM 1 (DOC 118 kb)


  1. 1.
    Schoen RE, Pinsky PF, Weissfeld JL, Yokochi LA, Church T, Laiyemo AO, et al. Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med. 2012;366:2345–57.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.CrossRefPubMedGoogle Scholar
  3. 3.
    Dean M. Cancer as a complex developmental disorder–nineteenth Cornelius P. Rhoads Memorial Award Lecture. Cancer Res. 1998;58:5633–6.PubMedGoogle Scholar
  4. 4.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  5. 5.
    Liang HH, Wei PL, Hung CS, Wu CT, Wang W, Huang MT, et al. MicroRNA-200a/b influenced the therapeutic effects of curcumin in hepatocellular carcinoma (HCC) cells. Tumour Biol. 2013;34:3209–18.CrossRefPubMedGoogle Scholar
  6. 6.
    Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94:776–80.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bienertova-Vasku J, Mazanek P, Hezova R, Curdova A, Nekvindova J, Kren L, et al. Extension of microRNA expression pattern associated with high-risk neuroblastoma. Tumour Biol. 2013;34:2315–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Yang L, Belaguli N, Berger DH. MicroRNA and colorectal cancer. World J Surg. 2009;33:638–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Petrocca F, Vecchione A, Croce CM. Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. Cancer Res. 2008;68:8191–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Yang IP, Tsai HL, Hou MF, Chen KC, Tsai PC, Huang SW, et al. MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle. Carcinogenesis. 2012;33:1522–30.CrossRefPubMedGoogle Scholar
  11. 11.
    Fang L, Du WW, Yang W, Rutnam ZJ, Peng C, Li H, et al. MiR-93 enhances angiogenesis and metastasis by targeting LATS2. Cell Cycle. 2012;11:4352–65.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, et al. MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-beta8. Oncogenesis. 2011;30:806–21.CrossRefGoogle Scholar
  13. 13.
    Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.CrossRefPubMedGoogle Scholar
  14. 14.
    Hu X, Li L, Shang M, Zhou J, Song X, Lu X, et al. Association between microRNA genetic variants and susceptibility to colorectal cancer in Chinese population. Tumour Biol. 2014;35:2151–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000;24:245–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov. 2006;5:997–1014.CrossRefPubMedGoogle Scholar
  17. 17.
    Huang K, Zhang JX, Han L, You YP, Jiang T, Pu PY, et al. MicroRNA roles in beta-catenin pathway. Mol Cancer. 2010;9:252.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Brabletz T, Jung A, Hermann K, Gunther K, Hohenberger W, Kirchner T. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract. 1998;194:701–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Edlund S, Lee SY, Grimsby S, Zhang S, Aspenstrom P, Heldin CH, et al. Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. Mol Cell Biol. 2005;25:1475–88.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Li Q, Zou C, Zou C, Han Z, Xiao H, Wei H, et al. MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7. Cancer Lett. 2013;335:168–74.CrossRefPubMedGoogle Scholar
  21. 21.
    Xiao ZG, Deng ZS, Zhang YD, Zhang Y, Huang ZC. Clinical significance of microRNA-93 downregulation in human colon cancer. Eur J Gastroenterol Hepatol. 2013;25:296–301.CrossRefPubMedGoogle Scholar
  22. 22.
    Mandel K, Seidl D, Rades D, Lehnert H, Gieseler F, Hass R, et al. Characterization of spontaneous and TGF-beta-induced cell motility of primary human normal and neoplastic mammary cells in vitro using novel real-time technology. PLoS One. 2013;8:e56591.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang Y, Tang Q, Li M, Jiang S, Wang X. MicroRNA-375 inhibits colorectal cancer growth by targeting PIK3CA. Biochem Biophys Res Commun. 2014;444:199–204.CrossRefPubMedGoogle Scholar
  24. 24.
    Halder SK, Rachakonda G, Deane NG, Datta PK. Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer. 2008;99:957–65.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Slattery ML, Herrick J, Curtin K, Samowitz W, Wolff RK, Caan BJ, et al. Increased risk of colon cancer associated with a genetic polymorphism of SMAD7. Cancer Res. 2010;70:1479–85.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Scholer-Dahirel A, McLaughlin ME. Determinants of Wnt/beta-catenin pathway dependency in colorectal cancer. Cell Cycle. 2012;11:9–10.CrossRefPubMedGoogle Scholar
  27. 27.
    Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012;18:892–901.CrossRefPubMedGoogle Scholar
  28. 28.
    Guo Q, Shen S, Liao M, Lian P, Wang X. NGX6 inhibits cell invasion and adhesion through suppression of Wnt/beta-catenin signal pathway in colon cancer. Acta Biochim Biophys Sin (Shanghai). 2010;42:450–6.CrossRefGoogle Scholar
  29. 29.
    Sivadas VP, Kannan S. The microRNA networks of TGFbeta signaling in cancer. Tumour Biol. 2014;35:2857–69.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Qingchao Tang
    • 1
  • Zhaoxia Zou
    • 2
  • Chendan Zou
    • 2
  • Qian Zhang
    • 1
  • Rui Huang
    • 1
  • Xu Guan
    • 1
  • Qiang Li
    • 3
  • Zhongjing Han
    • 2
  • Dayong Wang
    • 2
  • Huiyan Wei
    • 2
  • Xu Gao
    • 2
  • Xishan Wang
    • 1
    • 4
  1. 1.Department of Colorectal Cancer Surgery, Cancer Center, the Second Affiliated HospitalHarbin Medical UniversityHarbinChina
  2. 2.Department of Biochemistry and Molecular BiologyHarbin Medical UniversityHarbinChina
  3. 3.Department of General Surgery, the Second Affiliated HospitalHarbin Medical UniversityHarbinChina
  4. 4.Colorectal Cancer Institute, the Second Affiliated HospitalHarbin Medical UniversityHarbinChina

Personalised recommendations