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Olena Masui,
Nicole M A White,
Leroi V Desouza,
Olga Krakovska,
Ajay Matta,
Shereen Metias, Bishoy Khalil,
Alexander D Romaschin,
R John Honey,
Robert Stewart,
Kenneth Pace,
Georg A Bjarnason,
K W Michael Siu,
George M Yousef
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ABSTRACT: Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant malignancies and patients have a dismal prognosis with <10% five-year survival rate. Identification of markers that can predict the potential of metastases will have a great impact in improving patient outcome. In this study, we used differential proteomics with isobaric tags for relative and absolute quantitation (iTRAQ) labeling and LC-MS/MS analysis to identify proteins that are differentially expressed in metastatic compared to primary RCC. We identified 1256 non-redundant proteins and 456 of these were quantified. Further analysis identified 29 proteins that were differentially expressed (12 overexpressed and 17 under expressed) in metastatic vs. primary RCC. Dysregulated protein expressions of profilin-1 (Pfn1), 14-3-3 zeta/delta (14-3-3ζ), and galectin-1 (Gal-1) were verified on two independent sets of tissues by western blot and immunohistochemical analysis. Hierarchical clustering analysis showed the protein expression profile specific for metastatic RCC can distinguish between aggressive and non-aggressive RCC. Pathway analysis showed that dysregulated proteins are involved in cellular processes related to tumor progression and metastasis. Furthermore, preliminary analysis using a small set of tumors showed that increased expression of Pfn1 is associated with poor outcome and is a potential prognostic marker in RCC. In addition, 14-3-3ζ and Gal-1 also showed higher expression in the tumors with poor prognosis compared to those with good prognosis. Dysregulated proteins in metastatic RCC represent potential prognostic markers for kidney cancer patients and a greater understanding of their involved biological pathways can serve as the foundation of the development of novel targeted therapies for metastatic RCC.
Molecular & Cellular Proteomics 10/2012; · 7.40 Impact Factor
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Hala Faragalla,
Youssef M Youssef,
Andreas Scorilas, Bishoy Khalil,
Nicole M A White,
Salvador Mejia-Guerrero,
Heba Khella,
Michael A S Jewett,
Andrew Evans,
Zsuzsanna Lichner,
Georg Bjarnason,
Linda Sugar,
Magdy I Attalah,
George M Yousef
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ABSTRACT: Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. Increasing evidence suggests that microRNAs are dysregulated in RCC and are important factors in RCC pathogenesis. miR-21 is a known oncogene with tumor-promoting effects in many types of cancer. In this study, we analyzed miR-21 in 121 cases of healthy kidney and different RCC subtypes, including clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC), and oncocytoma. Total RNA was extracted, and the expression of miR-21 was measured with real-time quantitative RT-PCR using miR-21-specific probes. The expression of miR-21 was significantly up-regulated in RCC compared with healthy kidney. There was a significant difference in the expression levels between RCC subtypes, with the highest levels of expression in ccRCC and pRCC subtypes. miR-21 expression distinguished ccRCC and pRCC from chRCC and oncocytoma with 90% specificity (95% CI, 63.9% to 98.1%) and 83% sensitivity (95% CI, 53.5% to 97.6%). Significantly higher miR-21 levels were associated with higher stage and grade. Patients who were miR-21 positive had statistically significant shorter disease-free and overall survival rates. Thus, miR-21 is up-regulated in RCC, and its expression levels can be used as a diagnostic marker to distinguish ccRCC and pRCC from chRCC and oncocytoma. Moreover, it has potential as a prognostic marker in RCC, although it is not independent of tumor stage and grade.
The Journal of molecular diagnostics: JMD 05/2012; 14(4):385-92. · 3.48 Impact Factor
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Constantina Petraki,
Youssef M Youssef,
William Dubinski,
Zsuzsanna Lichner,
Andreas Scorilas,
Maria D Pasic,
Vassilios Komborozos, Bishoy Khalil,
Catherine Streutker,
Eleftherios P Diamandis,
George M Yousef
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ABSTRACT: The prognosis of patients with colorectal cancer (CRC) is assessed through conventional clinicopathological parameters, which are not always accurate. Members of the human kallikrein-related peptidases gene family represent potential cancer biomarkers. The aim of this study was to investigate the expression of human tissue kallikrein-related peptidase 10 (KLK10) by immunohistochemistry in CRC, to correlate this expression with various histopathological and clinical variables, and to evaluate its significance as a predictor of disease outcome. KLK10 expression was evaluated by immunohistochemistry and a combined expression score was calculated for each case based on intensity and percentage of positivity. A statistically significant positive association was observed between KLK10 and tumor stage and liver metastases (p = 0.015 and p = 0.035, respectively). Paradoxically, a negative association was observed between KLK10 and tumor grade (p = 0.009). Kaplan-Meier survival curves and univariate analysis showed that both KLK10 expression and stage had statistically significant correlations with disease-free survival (DFS) (p = 0.030 and p < 0.001, respectively) and overall survival (p = 0.010 and p = 0.001, respectively). Cox multivariate analysis showed that both KLK10 expression and stage were independent predictors of unfavorable DFS (p = 0.057 and p = 0.001, respectively) and overall survival (p = 0.009 and p = 0.001, respectively). In conclusion, KLK10 immunostaining is an independent prognostic marker in patients with CRC.
Tumor Biology 03/2012; 33(4):1209-14. · 1.94 Impact Factor
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Constantina Petraki,
William Dubinski,
Andreas Scorilas,
Carol Saleh,
Maria D Pasic,
Vassilios Komborozos, Bishoy Khalil,
Manal Y Gabril,
Catherine Streutker,
Eleftherios P Diamandis,
George M Yousef
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ABSTRACT: The prognosis of patients with colorectal cancer (CRC) is assessed through conventional clinicopathological parameters, which are not always accurate. Members of the human kallikrein-related peptidases gene family represent potential cancer biomarkers. The aim of this study was to investigate the expression of human tissue kallikrein-related peptidase 6 (KLK6) by immunohistochemistry in CRC to correlate this expression with various histopathological and clinical variables, and to evaluate its significance as a predictor of disease outcome. KLK6 expression was evaluated by immunohistochemistry and an expression score was calculated for each case. In CRC, KLK6 expression was decreased compared to normal colonic mucosa. A statistically significant, positive association was observed between KLK6 and tumor stage (p=0.036), lymph node metastases (p=0.030), and liver metastases (p=0.025). Univariate analysis showed that KLK6 expression and stage had statistically significant correlation with disease-free survival (p=0.045 and p<0.001, respectively) and overall survival (p=0.027 and p<0.001, respectively). Cox multivariate analysis showed that KLK6 expression was an independent predictor of unfavorable overall survival (p=0.041). Kaplan-Meier survival curves showed that KLK6-positive patients have statistically significant lower disease-free and overall survival. In conclusion, KLK6 immunostaining is an independent prognostic marker in patients with CRC.
Pathology - Research and Practice 02/2012; 208(2):104-8. · 1.21 Impact Factor
