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. Khella
  • Nicole M. A. White
  • Hala Faragalla
  • Manal Gabril
  • Mina Boazak
  • David Dorian
  • Bishoy Khalil
  • Hany Antonios
  • Tian Tian Bao
  • Maria D. Pasic
  • R. John Honey
  • Robert Stewart
  • Kenneth T. Pace
  • Georg A. Bjarnason
  • Michael A. S. Jewett
  • George M. Yousef
Research Article

DOI: 10.1007/s13277-011-0255-5

Cite this article as:
Khella, H.W.Z., White, N.M.A., Faragalla, H. et al. Tumor Biol. (2012) 33: 131. doi:10.1007/s13277-011-0255-5

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 carcinomaVEGF-AMicroRNATumour markersMetastasisPrognosis

Abbreviations

ccRCC

Clear cell renal cell carcinoma

EMT

Epithelial to mesenchymal

miRNA

microRNA

qRT-PCR

Quantitative reverse transcription polymerase chain reaction

RCC

Renal cell carcinoma

VEGF

Vascular endothelial growth factor

RPLPO

Acidic ribosomal phosphoprotein

EGFL7

Epidermal growth factor like 7

FAK

Focal adhesion kinase

IGF1

Targeting insulin-like growth factor 1

MMP2

Matrix metalopeptidase 2

HIF1A

Hypoxia inducible factor 1 alpha subunit

PDGFB

Platelet-derived growth factor B

PDGFC

Platelet-derived growth factor C

MDM2

Murine double minute 2

TYMS

Thymidylate synthase

VHL

Von Hippel Lindau

Supplementary material

13277_2011_255_MOESM1_ESM.doc (58 kb)
Supplementary Table 1The 40 top dysregulated miRNAs in metastatic ccRCC compared to primary tumours (DOC 58 kb)
13277_2011_255_MOESM2_ESM.doc (176 kb)
Supplementary Table 2Genes involved in Metastasis of different types of cancers are predicted targets of metastatic ccRCC miRNAs (DOC 175 kb)
13277_2011_255_MOESM3_ESM.doc (174 kb)
Supplementary Table 3Clusters of miRNA dysregulated in Metastasis (DOC 174 kb)
13277_2011_255_MOESM4_ESM.doc (116 kb)
Supplementary Table 4Intronic miRNAs and their host genes differentially expressed in ccRCC metastasis (DOC 116 kb)

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  • Heba W. Z. Khella
    • 1
    • 2
  • Nicole M. A. White
    • 1
    • 3
  • Hala Faragalla
    • 1
    • 3
  • Manal Gabril
    • 4
  • Mina Boazak
    • 1
  • David Dorian
    • 1
  • Bishoy Khalil
    • 1
  • Hany Antonios
    • 1
  • Tian Tian Bao
    • 1
  • Maria D. Pasic
    • 3
  • R. John Honey
    • 5
  • Robert Stewart
    • 5
  • Kenneth T. Pace
    • 5
  • Georg A. Bjarnason
    • 6
  • Michael A. S. Jewett
    • 7
  • George M. Yousef
    • 1
    • 3
  1. 1.Department of Laboratory Medicine and the Keenan Research CentreLi Ka Shing Knowledge Institute of St. Michael’s HospitalTorontoCanada
  2. 2.Institute of Medical Science, University of TorontoTorontoCanada
  3. 3.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  4. 4.Department of PathologyLondon Health Sciences CentreLondonCanada
  5. 5.Division of Urology, St. Michael’s HospitalTorontoCanada
  6. 6.Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer CenterTorontoCanada
  7. 7.Department of Surgery, Division of Urologic Oncology, Princess Margaret Hospital, University Health NetworkUniversity of TorontoTorontoCanada