miRNA Profiling in Metastatic Renal Cell Carcinoma Reveals a Tumor Suppressor Effect for miR-215
Nicole MA White, Heba WZ Khella, Jorg Grigull, Sonja Adzovic, Youssef M Youssef, R John Honey, Robert Stewart, Kenneth T Pace, Georg A Bjarnason, Michael AS Jewett, Andrew J Evans, Manal Gabril, George M Yousef. St. Michael's Hospital, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; York University, Toronto, ON, Canada; Sunnybrook Health Sciences Center, Toronto, ON, Canada; Princess Margaret Hospital, Toronto, ON, Canada; London Health Sciences Center, London, ON, Canada
Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The five-year survival rate for metastatic RCC is <10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer.
Design: We preformed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared to primary RCC. Results were validated by quantitative real time PCR. Target prediction analysis and gene expression profiling identified many of the dysregulated miRNAs could target genes involved in tumor metastasis. The effect of miR-215 on cellular migration and invasion was shown in a RCC cell line model.
Results: We identified 65 miRNAs that were significantly altered in metastatic when compared to primary RCC. Nine (14%) miRNAs had increased expression while 56 (86%) miRNAs showed decreased expression. miR-10b, miR-196a, and miR-27b were the most downregulated while miR-638, miR-1915, and miR-149* were the most upregulated. A non-supervised 2D-cluster analysis showed that a sub-group of the primary tumors clustered under the metastatic arm with a group of miRNAs that follow the same pattern of expression suggesting they have an inherited aggressive signature. We validated our results by examining the expressions of miR-10b, miR-126, miR-196a, miR-204, and miR-215, in two independent cohorts of patients. We also showed that overexpression of miR-215 decreased cellular migration and invasion in a RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumor metastasis.
Conclusions: Our analysis showed that miRNAs are altered in metastatic RCC and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.
Category: Genitourinary (including renal tumors)
Tuesday, March 20, 2012 11:00 AM
Platform Session: Section A, Tuesday Morning