microRNA Regulation of VHL Gene in Clear Cell Renal Cell Carcinomas
VA Valera, BA Walter, WM Linehan, ME Sobel, MJ Merino. National Cancer Institute, Bethesda, MD; American Society of Investigative Pathology, Bethesda, MD
Background: Loss of expression of the tumor suppressor gene VHL is a well known mechanism in the pathogenesis of hereditary and sporadic Renal Cell carcinomas (RCCs). In the disease, VHL silencing has been found to be mediated by either mutations or gene promoter methylation. However, the role of microRNA expression on VHL inactivation and therefore their influence on the onset and progression of RCCs has not been investigated yet. Therefore, the aim of this study was to evaluate the role of microRNAs on VHL gene inactivation and its correlation with clinicopathogic features in clear cell RCCs.
Design: Database search identified two microRNAs as potential regulators of the VHL gene by base pair complementarity: Hs-miR-320 and hs-miR-92. These two microRNAs and the target gene were analyzed by real-time PCR in a series of clear cell RCC and their corresponding paired normal tissue from FFPE tissue sections. A two-fold change (Up or down) in the Tumor-to Normal ratio (T/N) was determined as significant. MicroRNA expression was also correlated to the clinicopathologic features of the tumors. The relationship between these variables was evaluated by the Mann-Whitney or Kruskall-Wallis non-parametric tests and significance was defined as p<0.05.
Results: Ten cases of clear cell RCC were analyzed. Ninety percent of the tumors showed increased expression of miRNA-320 compared to the corresponding normal tissue with a median increase of the Tumor-to-Normal expression ratio of 5.35 fold. The pattern of expression for miRNA-92 was more heterogeneous with only 40% of the tumors showing overexpression. High expression of miRNA-320 correlated consistently (p<0.05) with a decreased expression of VHL gene protein and mRNA, and higher expression levels were found in cases with a higher Fuhrman nuclear grade (Median miRNA-320 T/N ratio= 4.35 in Fuhrman III cases vs.3.93 in Fuhrman II; p=0.670) and in female patients (5.57 vs. 1.83; p=0.05).
Conclusions: This is the first report of microRNA regulation of the VHL gene in kidney cancer, where overexpression of miRNA-320 appeared as an additional mechanism involved in VHL mRNA gene regulation in clear cell RCCs. Since hsa-miR-320 is also predicted to regulate other key factors in the VHL pathway, the reuslts have a great impact on disease diagnostics, monitoring and therapy.
Category: Special Category for 2009 - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 237, Tuesday Morning