Tumor Biology

, Volume 36, Issue 9, pp 6973–6983 | Cite as

Interference with the β-catenin gene in gastric cancer induces changes to the miRNA expression profile

  • Li Dong
  • Jun Deng
  • Ze-Min Sun
  • An-Ping Pan
  • Xiao-Jun Xiang
  • Ling Zhang
  • Feng Yu
  • Jun Chen
  • Zhe Sun
  • Miao Feng
  • Jian-Ping XiongEmail author
Research Article


Aberrant activation of the Wnt/β-catenin signaling pathway plays a major role in carcinogenesis and the progression of many malignant tumors, especially gastric cancer (GC). Some research has suggested that expression of the β-catenin protein is associated with clinicopathologic factors and affects the biological behaviors of GC cells. However, the mechanism of these effects is not yet clear. Studies show that the Wnt/β-catenin pathway regulates some miRNAs. We hypothesize that oncogenic activation of β-catenin signaling is involved in the formation of GC through regulating certain microRNAs (miRNAs). The results of the current study demonstrate that expression of the β-catenin protein is associated with many clinicopathologic characteristics including the degree of differentiation, depth of tumor invasion, tumor site, and 5-year survival rate. We found that silencing the expression of β-catenin with lentiviruses could delay cell proliferation, promote apoptosis, weaken the invasive power of GC cells, and increase the sensitivity of GC cells to 5-fluorouracil in vitro. Using miRNA microarrays to detect changes in the miRNA transcriptome following interference with β-catenin in GC cells, we found that miR-1234-3p, miR-135b-5p, miR-210, and miR-4739 were commonly upregulated and that miR-20a-3p, miR-23b-5p, miR-335-3p, miR-423-5p, and miR-455-3p were commonly downregulated. These data provide a theoretical basis for the potential interaction between miRNA and the β-catenin signaling pathway in GC.


Gastric cancer β-Catenin miRNA Signaling pathway 



The present study was supported by the JiangXi Province Talent 555 Project and the National Natural Science Foundation of China (nos. 81160281 and 81441083).

Conflicts of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392(6674):402–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Stadtlander CT, Waterbor JW. Molecular epidemiology, pathogenesis and prevention of gastric cancer. Carcinogenesis. 1999;20(12):2195–208.CrossRefPubMedGoogle Scholar
  4. 4.
    Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149(6):1192–205.CrossRefPubMedGoogle Scholar
  5. 5.
    Kim B, Byun SJ, Kim YA, Kim JE, Lee BL, et al. Cell cycle regulators, APC/beta-catenin, NF-kappaB and Epstein-Barr virus in gastric carcinomas. Pathology. 2010;42(1):58–65.CrossRefPubMedGoogle Scholar
  6. 6.
    Woo DK, Kim HS, Lee HS, Kang YH, Yang HK, et al. Altered expression and mutation of beta-catenin gene in gastric carcinomas and cell lines. Int J Cancer. 2001;95(2):108–13.CrossRefPubMedGoogle Scholar
  7. 7.
    Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, et al. beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 2002;62(12):3503–6.PubMedGoogle Scholar
  8. 8.
    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69.CrossRefPubMedGoogle Scholar
  9. 9.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMedGoogle Scholar
  10. 10.
    Spizzo R, Nicoloso MS, Croce CM, Calin GA. SnapShot: microRNAs in cancer. Cell. 2009;137(3):586–586 e1.CrossRefPubMedGoogle Scholar
  11. 11.
    Martello G, Zacchigna L, Inui M, Montagner M, Adorno M, et al. MicroRNA control of nodal signalling. Nature. 2007;449(7159):183–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Kapinas K, Kessler CB, Delany AM. miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling. J Cell Biochem. 2009;108(1):216–24.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kapinas K, Kessler C, Ricks T, Gronowicz G, Delany AM. miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. J Biol Chem. 2010;285(33):25221–31.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Schepeler T, Holm A, Halvey P, Nordentoft I, Lamy P, et al. Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes. Oncogene. 2012;31(22):2750–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Wang X, Lam EK, Zhang J, Jin H, Sung JJ. MicroRNA-122a functions as a novel tumor suppressor downstream of adenomatous polyposis coli in gastrointestinal cancers. Biochem Biophys Res Commun. 2009;387(2):376–80.CrossRefPubMedGoogle Scholar
  16. 16.
    Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell. 2000;103(2):311–20.CrossRefPubMedGoogle Scholar
  17. 17.
    Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, et al. Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol. 2010;176(6):2911–20.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Uren A, Fallen S, Yuan H, Usubutun A, Kucukali T, et al. Activation of the canonical Wnt pathway during genital keratinocyte transformation: a model for cervical cancer progression. Cancer Res. 2005;65(14):6199–206.CrossRefPubMedGoogle Scholar
  19. 19.
    Tanaka S, Arii S. Molecular targeted therapies in hepatocellular carcinoma. Semin Oncol. 2012;39(4):486–92.CrossRefPubMedGoogle Scholar
  20. 20.
    Li LF, Wei ZJ, Sun H, Jiang B. Abnormal beta-catenin immunohistochemical expression as a prognostic factor in gastric cancer: a meta-analysis. World J Gastroenterol. 2014;20(34):12313–21.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cheng XX, Wang ZC, Chen XY, Sun Y, Kong QY, et al. Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumour dissemination. Cancer Lett. 2005;223(2):339–47.CrossRefPubMedGoogle Scholar
  22. 22.
    Jawhari A, Jordan S, Poole S, Browne P, Pignatelli M, et al. Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma: relationship with patient survival. Gastroenterology. 1997;112(1):46–54.CrossRefPubMedGoogle Scholar
  23. 23.
    Pirinen RT, Hirvikoski P, Johansson RT, Hollmen S, Kosma VM. Reduced expression of alpha-catenin, beta-catenin, and gamma-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol. 2001;54(5):391–5.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Imura J, Ichikawa K, Takeda J, Fujimori T. Beta-catenin expression as a prognostic indicator in cervical adenocarcinoma. Int J Mol Med. 2001;8(4):353–8.PubMedGoogle Scholar
  25. 25.
    Lu W, Jia G, Meng X, Zhao C, Zhang L, et al. Beta-catenin mediates the apoptosis induction effect of celastrol in HT29 cells. Life Sci. 2012;91(7–8):279–83.CrossRefPubMedGoogle Scholar
  26. 26.
    Moon RT, Bowerman B, Boutros M, Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science. 2002;296(5573):1644–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Dang CV, O’Donnell KA, Zeller KI, Nguyen T, Osthus RC, et al. The c-Myc target gene network. Semin Cancer Biol. 2006;16(4):253–64.CrossRefPubMedGoogle Scholar
  28. 28.
    Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A. 1999;96(10):5522–7.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993;7(5):812–21.CrossRefPubMedGoogle Scholar
  30. 30.
    Geho DH, Bandle RW, Clair T, Liotta LA. Physiological mechanisms of tumor-cell invasion and migration. Physiology (Bethesda). 2005;20:194–200.CrossRefGoogle Scholar
  31. 31.
    Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T. Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol. 1999;155(4):1033–8.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sprio AE, Di Scipio F, Ceppi P, Salamone P, Di Carlo F, et al. Differentiation-inducing factor-1 enhances 5-fluorouracil action on oral cancer cells inhibiting E2F1 and thymidylate synthase mRNAs accumulation. Cancer Chemother Pharmacol. 2012;69(4):983–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Stein U, Fleuter C, Siegel F, Smith J, Kopacek A, et al. Impact of mutant beta-catenin on ABCB1 expression and therapy response in colon cancer cells. Br J Cancer. 2012;106(8):1395–405.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    He XP, Shao Y, Li XL, Xu W, Chen GS, et al. Downregulation of miR-101 in gastric cancer correlates with cyclooxygenase-2 overexpression and tumor growth. FEBS J. 2012;279(22):4201–12.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhou L, Qiu T, Xu J, Wang T, Wang J, et al. miR-135a/b modulate cisplatin resistance of human lung cancer cell line by targeting MCL1. Pathol Oncol Res. 2013;19(4):677–83.CrossRefPubMedGoogle Scholar
  36. 36.
    Golubovskaya VM, Sumbler B, Ho B, Yemma M, Cance WG. MiR-138 and MiR-135 directly target focal adhesion kinase, inhibit cell invasion, and increase sensitivity to chemotherapy in cancer cells. Anticancer Agents Med Chem. 2014;14(1):18–28.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451(7175):147–52.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Xu Y, Zhao F, Wang Z, Song Y, Luo Y, et al. MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1. Oncogene. 2012;31(11):1398–407.CrossRefPubMedGoogle Scholar
  39. 39.
    Liu W, Zabirnyk O, Wang H, Shiao YH, Nickerson ML, et al. miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer. Oncogene. 2010;29(35):4914–24.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Zaman MS, Thamminana S, Shahryari V, Chiyomaru T, Deng G, et al. Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer. PLoS One. 2012;7(11), e50203.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Li X, Zhang Z, Yu M, Li L, Du G, et al. Involvement of miR-20a in promoting gastric cancer progression by targeting early growth response 2 (EGR2). Int J Mol Sci. 2013;14(8):16226–39.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Li Dong
    • 1
  • Jun Deng
    • 1
  • Ze-Min Sun
    • 1
  • An-Ping Pan
    • 1
  • Xiao-Jun Xiang
    • 1
  • Ling Zhang
    • 1
  • Feng Yu
    • 1
  • Jun Chen
    • 1
  • Zhe Sun
    • 1
  • Miao Feng
    • 1
  • Jian-Ping Xiong
    • 1
    Email author
  1. 1.Department of OncologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina

Personalised recommendations