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Adenomatous polyposis coli (APC) regulates miR17-92 cluster through β-catenin pathway in colorectal cancer

Oncogene volume 35, pages 4558–4568 (2016)Cite this article

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An Editorial Expression of Concern to this article was published on 20 February 2024

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Abstract

Adenomatous polyposis coli (APC) mutation is the most common genetic change in sporadic colorectal cancer (CRC). Although deregulations of miRNAs have been frequently reported in this malignancy, APC-regulated miRNAs have not been extensively documented. Here, by using an APC-inducible cell line and array analysis, we identified a total of 26 deregulated miRNAs. Among them, members of miR-17-92 cluster were dramatically inhibited by APC and induced by enforced expression of β-catenin. Furthermore, we demonstrate that activated β-catenin resulted from APC loss binds to and activates the miR-17-92 promoter. Notably, enforced expression of miR-19a overrides APC tumor suppressor activity, and knockdown of miR-19a in cancer cells with compromised APC function reduced their aggressive features in vitro. Finally, we observed that expression of miR-19a significantly correlates with β-catenin levels in colorectal cancer specimens, and it is associated to the aggressive stage of tumor progression. Thus, our study reveals that miR-17-92 cluster is directly regulated by APC/β-catenin pathway and could be a potential therapeutic target in colon cancers with aberrant APC/β-catenin signaling.

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References

  1. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B et al. Colorectal cancer. Lancet 2010; 375: 1030–1047.

    Article  Google Scholar 

  2. Markowitz SD, Bertagnolli MM . Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 2009; 361: 2449–2460.

    Article  CAS  Google Scholar 

  3. Mimori-Kiyosue Y, Matsui C, Sasaki H, Tsukita S . Adenomatous polyposis coli (APC) protein regulates epithelial cell migration and morphogenesis via PDZ domain-based interactions with plasma membranes. Genes Cells 2007; 12: 219–233.

    Article  CAS  Google Scholar 

  4. Phelps RA, Broadbent TJ, Stafforini DM, Jones DA . New perspectives on APC control of cell fate and proliferation in colorectal cancer. Cell Cycle 2009; 8: 2549–2556.

    Article  CAS  Google Scholar 

  5. Barth AI, Caro-Gonzalez HY, Nelson WJ . Role of adenomatous polyposis coli (APC) and microtubules in directional cell migration and neuronal polarization. Semin Cell Dev Biol 2008; 19: 245–251.

    Article  CAS  Google Scholar 

  6. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 1997; 275: 1784–1787.

    Article  CAS  Google Scholar 

  7. D'Uva G, Bertoni S, Lauriola M, De Carolis S, Pacilli A, D'Anello L et al. Beta-catenin/HuR post-transcriptional machinery governs cancer stem cell features in response to hypoxia. PLoS One 2013; 8: e80742.

    Article  Google Scholar 

  8. Ha NC, Tonozuka T, Stamos JL, Choi HJ, Weis WI . Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation. Mol Cell 2004; 15: 511–521.

    Article  CAS  Google Scholar 

  9. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P . Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 1996; 272: 1023–1026.

    Article  CAS  Google Scholar 

  10. Kudo Y, Kitajima S, Ogawa I, Hiraoka M, Sargolzaei S, Keikhaee MR et al. Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beta-catenin. Clin Cancer Res 2004; 10: 5455–5463.

    Article  CAS  Google Scholar 

  11. Pendas-Franco N, García JM, Peña C, Valle N, Pálmer HG, Heinäniemi M et al. DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3. Oncogene 2008; 27: 4467–4477.

    Article  CAS  Google Scholar 

  12. 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: 1787–1790.

    Article  CAS  Google Scholar 

  13. Ambros V . The functions of animal microRNAs. Nature 2004; 431: 350–355.

    Article  CAS  Google Scholar 

  14. Kong W, He L, Richards EJ, Challa S, Xu CX, Permuth-Wey J et al. Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene 2014; 33: 679–689.

    Article  CAS  Google Scholar 

  15. Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.

    Article  CAS  Google Scholar 

  16. Fish JE, Srivastava D . MicroRNAs: opening a new vein in angiogenesis research. Sci Signal 2009; 2: pe1.

    Article  Google Scholar 

  17. Tysnes BB . Tumour-initiating and -propagating cells: cells that we would like to identify and control. Neoplasia 2010; 12: 506–515.

    Article  CAS  Google Scholar 

  18. Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol 2010; 11: 136–146.

    Article  CAS  Google Scholar 

  19. Mogilyansky E, Rigoutsos I . The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ 2013; 20: 1603–1614.

    Article  CAS  Google Scholar 

  20. Zhou JJ, Zheng S, Sun LF, Zheng L . MicroRNA regulation network in colorectal cancer metastasis. World J Biol Chem 2014; 5: 301–307.

    Article  Google Scholar 

  21. Necela BM, Carr JM, Asmann YW, Thompson EA . Differential expression of microRNAs in tumours from chronically inflamed or genetic (APC(Min/+)) models of colon cancer. PLoS One 2011; 6: e18501.

    Article  CAS  Google Scholar 

  22. Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X et al. MicroRNA-221/222 negatively regulates estrogen receptor{alpha} and is associated with tamoxifen resistance in breast cancer. J Biol Chem 2008; 283: 31079–31086.

    Article  CAS  Google Scholar 

  23. Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 2008; 68: 425–433.

    Article  CAS  Google Scholar 

  24. Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 2008; 28: 6773–6784.

    Article  CAS  Google Scholar 

  25. Diosdado B, van de Wiel MA, Terhaar Sive Droste JS, Mongera S, Postma C, Meijerink WJ et al. MiR-17-92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma to adenocarcinoma progression. Br J Cancer 2009; 101: 707–714.

    Article  CAS  Google Scholar 

  26. Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P . Downregulation of beta-catenin by human Axin and its association with the APC tumour suppressor, beta-catenin and GSK3 beta. Curr Biol 1998; 8: 573–581.

    Article  CAS  Google Scholar 

  27. van Haaften G, Agami R . Tumourigenicity of the miR-17-92 cluster distilled. Genes Dev 2010; 24: 1–4.

    Article  CAS  Google Scholar 

  28. Jiang H, Wang P, Wang Q, Wang B, Mu J, Zhuang X et al. Quantitatively controlling expression of miR-17~92 determines colon tumor progression in a mouse tumor model. Am J Pathol 2014; 184: 1355–1368.

    Article  CAS  Google Scholar 

  29. Morin PJ, Vogelstein B, Kinzler KW . Apoptosis and APC in colorectal tumourigenesis. Proc Natl Acad Sci USA 1996; 93: 7950–7954.

    Article  CAS  Google Scholar 

  30. Miyazawa K, Iwaya K, Kuroda M, Harada M, Serizawa H, Koyanagi Y et al. Nuclear accumulation of beta-catenin in intestinal-type gastric carcinoma: correlation with early tumour invasion. Virchows Arch 2000; 437: 508–513.

    Article  CAS  Google Scholar 

  31. Grillari J, Hackl M, Grillari-Voglauer R . miR-17-92 cluster: ups and downs in cancer and aging. Biogerontology 2010; 11: 501–506.

    Article  CAS  Google Scholar 

  32. Lanza G, Ferracin M, Gafà R, Veronese A, Spizzo R, Pichiorri F et al. mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer. Mol Cancer 2007; 6: 54.

    Article  Google Scholar 

  33. Hong L, Lai M, Chen M, Xie C, Liao R, Kang YJ et al. The miR-17-92 cluster of microRNAs confers tumourigenicity by inhibiting oncogene-induced senescence. Cancer Res 2010; 70: 8547–8557.

    Article  CAS  Google Scholar 

  34. Yu G, Tang JQ, Tian ML, Li H, Wang X, Wu T et al. Prognostic values of the miR-17-92 cluster and its paralogs in colon cancer. J Surg Oncol 2012; 106: 232–237.

    Article  CAS  Google Scholar 

  35. Luo X, Burwinkel B, Tao S, Brenner H . MicroRNA signatures: novel biomarker for colorectal cancer? Cancer Epidemiol Biomarkers Prev 2011; 20: 1272–1286.

    Article  CAS  Google Scholar 

  36. Koga Y, Yasunaga M, Takahashi A, Kuroda J, Moriya Y, Akasu T et al. MicroRNA expression profiling of exfoliated colonocytes isolated from feces for colorectal cancer screening. Cancer Prev Res (Phila) 2010; 3: 1435–1442.

    Article  Google Scholar 

  37. Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 2009; 58: 1375–1381.

    Article  CAS  Google Scholar 

  38. O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT . c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005; 435: 839–843.

    Article  CAS  Google Scholar 

  39. Mu P, Han YC, Betel D, Yao E, Squatrito M, Ogrodowski P et al. Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev 2009; 23: 2806–2811.

    Article  CAS  Google Scholar 

  40. Tetsu O, McCormick F . Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422–426.

    Article  CAS  Google Scholar 

  41. Hulit J, Wang C, Li Z, Albanese C, Rao M, Di Vizio D et al. Cyclin D1 genetic heterozygosity regulates colonic epithelial cell differentiation and tumour number in ApcMin mice. Mol Cell Biol 2004; 24: 7598–7611.

    Article  CAS  Google Scholar 

  42. Olive V, Bennett MJ, Walker JC, Ma C, Jiang I, Cordon-Cardo C et al. miR-19 is a key oncogenic component of mir-17-92. Genes Dev 2009; 23: 2839–2849.

    Article  CAS  Google Scholar 

  43. Takahashi-Yanaga F, Sasaguri T . Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: inhibitors of the Wnt/beta-catenin signaling pathway as novel anticancer drugs. J Pharmacol Sci 2009; 109: 179–183.

    Article  CAS  Google Scholar 

  44. Takahashi-Yanaga F, Kahn M . Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 2010; 16: 3153–3162.

    Article  CAS  Google Scholar 

  45. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004; 5: 91–102.

    Article  CAS  Google Scholar 

  46. Song S, Christova T, Perusini S, Alizadeh S, Bao RY, Miller BW et al. Wnt inhibitor screen reveals iron dependence of beta-catenin signaling in cancers. Cancer Res 2011; 71: 7628–7639.

    Article  CAS  Google Scholar 

  47. Lindow M, Kauppinen S . Discovering the first microRNA-targeted drug. J Cell Biol 2012; 199: 407–412.

    Article  CAS  Google Scholar 

  48. Solmi R, Lauriola M, Francesconi M, Martini D, Voltattorni M, Ceccarelli C et al. Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines. BMC Cancer 2008; 8: 227.

    Article  Google Scholar 

  49. Smyth GK . Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004; 3: Article3.

    Article  Google Scholar 

  50. Shi XB, Xue L, Yang J, Ma AH, Zhao J, Xu M et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci USA 2007; 104: 19983–19988.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful for the Molecular Biology and Analytic Microscopy Core and Tissue Core facilities at H. Lee Moffitt Cancer Center. We also thank Dr Thomas Ried for providing NCI-H508 cell line. This work was supported in part by CA137041, CA160455 (JQC) and the Moffitt Cancer Center Foundation. The H. Lee Moffitt Cancer Center & Research Institute is supported in part by NCI Cancer Center Support Grant #P30 CA076292. ML was supported by ‘Fondazione del Monte di Bologna e di Ravenna’ (Bologna, Italy).

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Author notes

  1. T J Yeatman

    Present address: 7Current address: Gibbs Cancer Center and Research Institute, Spartanburg, SC, USA.,

  2. Y Li, M Lauriola and D Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Y Li, M Lauriola, D Kim & J Q Cheng

  2. Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy

    M Lauriola, G D’Uva & R Solmi

  3. EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), Dr. Aiguader, Barcelona, Spain

    M Francesconi

  4. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    D Shibata, M P Malafa & T J Yeatman

  5. Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    D Coppola

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Correspondence to D Coppola, R Solmi or J Q Cheng.

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Li, Y., Lauriola, M., Kim, D. et al. Adenomatous polyposis coli (APC) regulates miR17-92 cluster through β-catenin pathway in colorectal cancer. Oncogene 35, 4558–4568 (2016). https://doi.org/10.1038/onc.2015.522

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  • DOI: https://doi.org/10.1038/onc.2015.522

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