Invasive urothelial cell carcinoma (UCC) is associated with poor clinical outcome and is characterized by a genotype that is distinct from superficial disease. Exploiting a multi-component mining strategy on a set of high-throughput genome-wide experimental data, we probed for genes associated with an invasive phenotype. Fresh frozen UCC tissues were profiled using global expression microarrays and array-based comparative genomic hybridization (aCGH). Differentially expressed genes were functionally annotated by gene ontology and compared to available SAGE libraries and expression array datasets. We identified overexpression of a lipid raft associated protein, Flotillin 2 (FLOT2) in invasive UCC. The FLOT2 locus (17q11-q12) was associated with copy number gains in 15% of the tumors. We further characterized Flot2 protein expression in an independent tissue microarray series by immunohistochemistry. Flot2 protein expression increased with clinical risk. Interestingly, carcinoma in situ (CIS) tumors demonstrated highest level of expression. In vitro, FLOT2 expression increased with the degree of invasiveness of the UCC cell lines. Knockdown of FLOT2 lead to a significant reduction in the invasive phenotype; whilst overexpression of wild-type FLOT2 enhanced invasion in non-invasive cells. The precise mode of action of Flot2 remains to be elucidated but it is predicted to play an important role in transmembrane signal transduction, cell adhesion and endocytosis. FLOT2 overexpression has also been shown to enhance the spreading of cells, formation of filopodia as well as melanoma progression and metastasis. Thus, the functional targeting experiments and gene-dosage dependent FLOT2 overexpression in invasive UCC confirm a link between FLOT2 and pro-invasive cancer phenotype.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1191.

©2010 American Association for Cancer Research
2010