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Original article
The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis
  1. Hui Ling1,
  2. Karen Pickard2,
  3. Cristina Ivan3,
  4. Claudio Isella4,5,
  5. Mariko Ikuo1,6,
  6. Richard Mitter7,
  7. Riccardo Spizzo8,
  8. Marc D Bullock1,2,
  9. Cornelia Braicu9,
  10. Valentina Pileczki9,
  11. Kimberly Vincent1,
  12. Martin Pichler1,10,
  13. Verena Stiegelbauer10,
  14. Gerald Hoefler11,
  15. Maria I Almeida1,12,
  16. Annie Hsiao1,
  17. Xinna Zhang3,
  18. John N Primrose2,13,
  19. Graham K Packham2,
  20. Kevin Liu1,
  21. Krishna Bojja1,
  22. Roberta Gafà14,
  23. Lianchun Xiao15,
  24. Simona Rossi1,
  25. Jian H Song16,
  26. Ivan Vannini17,
  27. Francesca Fanini17,
  28. Scott Kopetz18,
  29. Patrick Zweidler-McKay19,
  30. Xuemei Wang15,
  31. Calin Ionescu20,21,
  32. Alexandru Irimie22,
  33. Muller Fabbri17,23,
  34. Giovanni Lanza14,
  35. Stanley R Hamilton24,
  36. Ioana Berindan-Neagoe9,25,
  37. Enzo Medico4,5,
  38. Alex H Mirnezami2,13,
  39. George A Calin1,3,
  40. Milena S Nicoloso1,8
  1. 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2Cancer Research UK Centre, University of Southampton Cancer Sciences Unit, Somers Cancer Research Building, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  3. 3Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  4. 4Department of Oncology, University of Torino, Torino, Italy
  5. 5IRCC, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy
  6. 6Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
  7. 7Bioinformatics Unit, London Research Institute, Cancer Research UK, London, UK
  8. 8Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano, Italy
  9. 9Department of Functional Genomics, The Oncology Institute, Cluj-Napoca, Romania
  10. 10Division of Oncology, Medical University of Graz, Graz, Austria
  11. 11Institute of Pathology, Medical University of Graz, Graz, Austria
  12. 12INEB, Instituto de Engenharia Biomedica, University of Porto, Porto, Portugal
  13. 13Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  14. 14Section of Pathology and Molecular Diagnostics, University of Ferrara, Ferrara, Italy
  15. 15Division of Quantitative Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
  16. 16Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  17. 17Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) s.r.l., IRCCS, Gene Therapy Unit, Meldola (FC), Italy
  18. 18Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  19. 19Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  20. 20Surgical Clinic 1, Cluj County Hospital, Romania
  21. 21UMF Surgery Department 1, Cluj-Napoca, Romania
  22. 22Department of Surgical and Gynecology Oncology, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania
  23. 23Departments of Pediatrics, and Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, The Saban Research Institute, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, USA
  24. 24Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  25. 25Department of Immunology and Research Center for Functional Genomics, Biomedicine and Translational Medicine University of Medicine and Pharmacy ‘I. Hatieganu’, Cluj-Napoca, Romania
  1. Correspondence to Dr George A Calin, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; gcalin{at}mdanderson.org Milena S Nicoloso, MD, Division of Experimental Oncology B, CRO, National Cancer Institute, Aviano, Italy; mnicoloso@cro.it Alex Mirnezami, MD, PhD, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD, UK; A.H.Mirnezami@soton.ac.uk.

Abstract

Objective MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis.

Design We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan–Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression.

Results MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=−0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175).

Conclusions MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.

  • COLORECTAL CANCER
  • MICROSATELLITE INSTABILITY
  • MOLECULAR GENETICS
  • RNA EXPRESSION
  • LIVER METASTASES

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