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

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Tumor Biology

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.

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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

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Acknowledgements

This work was supported by grants from the Canadian Institute of Health Research (CIHR grant # 86490), Canadian Cancer Society (CCS grant # 20185), the Ministry of Research and Innovation, Government of Ontario, the Kidney Foundation of Canada and Cancer Research Society.

Conflicts of interest

None

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Authors and Affiliations

  1. Department of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Heba W. Z. Khella, Nicole M. A. White, Hala Faragalla, Mina Boazak, David Dorian, Bishoy Khalil, Hany Antonios, Tian Tian Bao & George M. Yousef

  2. Institute of Medical Science, University of Toronto, Toronto, Canada, M5S 1A8

    Heba W. Z. Khella

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada, M5S 1A8

    Nicole M. A. White, Hala Faragalla, Maria D. Pasic & George M. Yousef

  4. Department of Pathology, London Health Sciences Centre, London, Canada, N6A 5W9

    Manal Gabril

  5. Division of Urology, St. Michael’s Hospital, Toronto, Canada, M5B 1W8

    R. John Honey, Robert Stewart & Kenneth T. Pace

  6. Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Center, Toronto, ON, M4N 3M5, Canada

    Georg A. Bjarnason

  7. Department of Surgery, Division of Urologic Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Canada

    Michael A. S. Jewett

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  1. Heba W. Z. Khella
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  2. Nicole M. A. White
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  3. Hala Faragalla
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  4. Manal Gabril
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  5. Mina Boazak
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  6. David Dorian
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  9. Tian Tian Bao
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  10. Maria D. Pasic
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  11. R. John Honey
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  15. Michael A. S. Jewett
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  16. George M. Yousef
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Corresponding author

Correspondence to George M. Yousef.

Electronic supplementary materials

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Supplementary Table 1

The 40 top dysregulated miRNAs in metastatic ccRCC compared to primary tumours (DOC 58 kb)

Supplementary Table 2

Genes involved in Metastasis of different types of cancers are predicted targets of metastatic ccRCC miRNAs (DOC 175 kb)

Supplementary Table 3

Clusters of miRNA dysregulated in Metastasis (DOC 174 kb)

Supplementary Table 4

Intronic miRNAs and their host genes differentially expressed in ccRCC metastasis (DOC 116 kb)

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Khella, H.W.Z., White, N.M.A., Faragalla, H. et al. Exploring the role of miRNAs in renal cell carcinoma progression and metastasis through bioinformatic and experimental analyses. Tumor Biol. 33, 131–140 (2012). https://doi.org/10.1007/s13277-011-0255-5

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