Quantitative proteomic analysis reveals potential diagnostic markers and pathways involved in pathogenesis of renal cell carcinoma
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Nicole M.A. White1,2,*, Olena Masui3,*, Leroi V. DeSouza3, Olga Krakovska3, Shereen Metias1, Alexander D. Romaschin1,2, R. John Honey4, Robert Stewart4, Kenneth Pace4, Jason Lee4, Michael AS Jewett5, Georg A. Bjarnason6, K.W. Michael Siu3, and George M. Yousef1,2
1 The Keenan Research Center in the Li Ka Shing Knowledge Institute and the Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, Canada
2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
3 Department of Chemistry and Centre for Research in Mass Spectrometry, York University, Toronto, Canada
4 Department of Surgery, St. Michael’s Hospital, Toronto, Canada
5 Division of Urologic Oncology, Princess Margaret Hospital, University Health Network, Department of Surgery, University of Toronto, Toronto, ON, Canada
6 Division of Medical Oncology and Hematology, Sunnybrook Health Sciences, Toronto, Canada
* These authors contributed equally to the manuscript
George M Yousef, email:
Keywords: kidney cancer, renal cell, carcinoma, iTRAQ, proteomics, Hsp27, urine markers
Received: October 21, 2013 Accepted: January 18, 2014 Published: January 18, 2014
There are no serum biomarkers for the accurate diagnosis of clear cell renal cell carcinoma (ccRCC). Diagnosis and decision of nephrectomy rely on imaging which is not always accurate. Non-invasive diagnostic biomarkers are urgently required. In this study, we preformed quantitative proteomics analysis on a total of 199 patients including 30 matched pairs of normal kidney and ccRCC using isobaric tags for relative and absolute quantitation (iTRAQ) labeling and LC-MS/MS analysis to identify differentially expressed proteins. We found 55 proteins significantly dysregulated in ccRCC compared to normal kidney tissue. 54 were previously reported to play a role in carcinogenesis, and 39 are secreted proteins. Dysregulation of alpha-enolase (ENO1), L-lactate dehydrogenase A chain (LDHA), heat shock protein beta-1 (HSPB1/Hsp27), and 10 kDa heat shock protein, mitochondrial (HSPE1) was confirmed in two independent sets of patients by western blot and immunohistochemistry. Pathway analysis, validated by PCR, showed glucose metabolism is altered in ccRCC compared to normal kidney tissue. In addition, we examined the utility of Hsp27 as biomarker in serum and urine. In ccRCC patients, Hsp27 was elevated in the urine and serum and high serum Hsp27 was associated with high grade (Grade 3-4) tumors. These data together identify potential diagnostic biomarkers for ccRCC and shed new light on the molecular mechanisms that are dysregulated and contribute to the pathogenesis of ccRCC. Hsp27 is a promising diagnostic marker for ccRCC although further large-scale studies are required. Also, molecular profiling may help pave the road to the discovery of new therapies.
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