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

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Tumor Biology

Abstract

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.

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References

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  3. Stadtlander CT, Waterbor JW. Molecular epidemiology, pathogenesis and prevention of gastric cancer. Carcinogenesis. 1999;20(12):2195–208.

    Article  CAS  PubMed  Google Scholar 

  4. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149(6):1192–205.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  8. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69.

    Article  CAS  PubMed  Google Scholar 

  9. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

    Article  CAS  PubMed  Google Scholar 

  10. Spizzo R, Nicoloso MS, Croce CM, Calin GA. SnapShot: microRNAs in cancer. Cell. 2009;137(3):586–586 e1.

    Article  CAS  PubMed  Google Scholar 

  11. Martello G, Zacchigna L, Inui M, Montagner M, Adorno M, et al. MicroRNA control of nodal signalling. Nature. 2007;449(7159):183–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  16. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell. 2000;103(2):311–20.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  19. Tanaka S, Arii S. Molecular targeted therapies in hepatocellular carcinoma. Semin Oncol. 2012;39(4):486–92.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  30. Geho DH, Bandle RW, Clair T, Liotta LA. Physiological mechanisms of tumor-cell invasion and migration. Physiology (Bethesda). 2005;20:194–200.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

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

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Correspondence to Jian-Ping Xiong.

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Li Dong and Jun Deng contributed equally to this work.

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Dong, L., Deng, J., Sun, ZM. et al. Interference with the β-catenin gene in gastric cancer induces changes to the miRNA expression profile. Tumor Biol. 36, 6973–6983 (2015). https://doi.org/10.1007/s13277-015-3415-1

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  • DOI: https://doi.org/10.1007/s13277-015-3415-1

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