Research Article

Tumor Biology

, Volume 33, Issue 1, pp 131-140

Exploring the role of miRNAs in renal cell carcinoma progression and metastasis through bioinformatic and experimental analyses

  • Heba W. Z. KhellaAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s HospitalInstitute of Medical Science, University of Toronto
  • , Nicole M. A. WhiteAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s HospitalDepartment of Laboratory Medicine and Pathobiology, University of Toronto
  • , Hala FaragallaAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s HospitalDepartment of Laboratory Medicine and Pathobiology, University of Toronto
  • , Manal GabrilAffiliated withDepartment of Pathology, London Health Sciences Centre
  • , Mina BoazakAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital
  • , David DorianAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital
  • , Bishoy KhalilAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital
  • , Hany AntoniosAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital
  • , Tian Tian BaoAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital
    • , Maria D. PasicAffiliated withDepartment of Laboratory Medicine and Pathobiology, University of Toronto
    • , R. John HoneyAffiliated withDivision of Urology, St. Michael’s Hospital
    • , Robert StewartAffiliated withDivision of Urology, St. Michael’s Hospital
    • , Kenneth T. PaceAffiliated withDivision of Urology, St. Michael’s Hospital
    • , Georg A. BjarnasonAffiliated withDivision of Medical Oncology and Hematology, Sunnybrook Odette Cancer Center
    • , Michael A. S. JewettAffiliated withDepartment of Surgery, Division of Urologic Oncology, Princess Margaret Hospital, University Health Network, University of Toronto
    • , George M. YousefAffiliated withDepartment of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s HospitalDepartment of Laboratory Medicine and Pathobiology, University of Toronto Email author 

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Abstract

Metastasis results in most of the cancer deaths in clear cell renal cell carcinoma (ccRCC). MicroRNAs (miRNAs) regulate many important cell functions and play important roles in tumor development, metastasis and progression. In our previous study, we identified a miRNA signature for metastatic RCC. In this study, we validated the top differentially expressed miRNAs on matched primary and metastatic ccRCC pairs by quantitative polymerase chain reaction. We performed bioinformatics analyses including target prediction and combinatorial analysis of previously reported miRNAs involved in tumour progression and metastasis. We also examined the co-expression of the miRNAs clusters and compared expression of intronic miRNAs and their host genes. We observed significant dysregulation between primary and metastatic tumours from the same patient. This indicates that, at least in part, the metastatic signature develops gradually during tumour progression. We identified metastasis-dysregulated miRNAs that can target a number of genes previously found to be involved in metastasis of kidney cancer as well as other malignancies. In addition, we found a negative correlation of expression of miR-126 and its target vascular endothelial growth factor (VEGF)-A. Cluster analysis showed that members of the same miRNA cluster follow the same expression pattern, suggesting the presence of a locus control regulation. We also observed a positive correlation of expression between intronic miRNAs and their host genes, thus revealing another potential control mechanism for miRNAs. Many of the significantly dysregulated miRNAs in metastatic ccRCC are highly conserved among species. Our analysis suggests that miRNAs are involved in ccRCC metastasis and may represent potential biomarkers.

Keywords

Renal cell carcinoma VEGF-A MicroRNA Tumour markers Metastasis Prognosis