Loss of microRNA-205 Expression Is Associated with Melanoma Progression
Michael T Tetzlaff, Shujing Liu, Aihua Liu, Bernadette Liegl-Atzwanger, Xiaowei Xu. The University of Texas MD Anderson Cancer Center, Houston, TX; The Hospital of the University of Pennsylvania, Philadelphia, PA; The University of Graz, Graz, Austria
Background: Melanoma remains the most deadly of the common forms of skin cancer: ∼8700 people died of melanoma in 2010, accounting for ∼70% of all skin cancer related deaths. There is therefore a critical need to identify clinically informative biomarkers that illuminate those biochemical pathways central to the aggressive behavior of melanoma, since these will provide new targets for the design of rational therapeutic interventions. microRNAs (miRNAs) are short, non-coding RNAs that function in post-transcriptional gene regulatory pathways. Alterations in miRNA expression have been described in many different human tumors, and miRNAs function as key pathogenic components impacting cancer cell growth, survival and the capacity to metastasize. Moreover, it is feasible to obtain high-quality miRNA expression data from formalin-fixed paraffin embedded (FFPE) melanomas—often the only tissue available for retrospective analyses.
Design: We used archived FFPE specimens to define alterations in miRNA expression comparing nevi (n=10) to primary (n=10) to metastatic (n=10) melanomas using a microarray platform. We validated a discrete subset of changes in an independent set of nevi and melanomas by quantitative RT-PCR. Using melanoma cell lines, we characterized the function of one miRNA, miR-205, whose expression was progressively diminished from nevi to primary to metastatic melanomas.
Results: Enforced miR-205 expression in melanoma cells profoundly impairs cell motility and migration in vitro along with significantly decreased F-actin polymerization with only a modest reduction in cell proliferation. In an in vivo xenograft model, melanoma cells overexpressing miR-205 exhibit a reduced migratory capacity compared to control tumor cells. Mechanistically, miR-205 overexpression correlates with decreased expression of the zinc finger E-box binding homeobox 2 (ZEB2) mRNA and protein, and this coincides with increased expression of E-cadherin mRNA and protein.
Conclusions: Together, these results provide evidence for miR-205 as a suppressor of cell migration in the progression of malignant melanoma, and the dysregulation of miR-205 correlates with alterations in epithelial to mesenchymal transition pathways. The identification of differentially expressed miRNAs impacting melanoma cell biology will provide new potential therapeutic targets for the treatment of melanoma.
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 103, Wednesday Afternoon