Abstract
Abstract 4F2, a transmembrane protein, has a heteromeric structure, consisting of a heavy subunit (4F2hc, CD98hc, SLC3A2) and a light subunit, extracellular linked together via disulfid bounds. The light chains provide amino acid transport activity, while the heavy chain physically interacts with a conserved motif of integrin beta subunits, thereby mediating adhesion-induced signal transduction. A genetic knockout of 4F2hc in animals is embryonic lethal, overexpression of 4F2hc in somatic cells leads to malignant transformation. In the present study we aimed to characterize 4F2hc expression in renal cell cancer (RCC) as a diagnostic or prognostic marker, as well as to indentify a potential functional role of 4F2 in tumor cell behavior. By immunohistochemistry and analysis of multi tissue arrays, we found that 4F2hc is highly expressed in papillary, clear cell and chromophobe RCC, while no 4F2hc expression was found in benign tumors, such as oncocytomas. Thereby, 4F2hc expression directly correlated with grade of differentiation suggesting 4F2hc as a novel and reliable marker for the more malignant subtype II papillary renal cell cancer (type II 83.34 %, type I 4.76 % 4F2hc positive, p < 0.00001; n = 51). To evaluate a potential functional role of 4F2 in renal cancer cell behavior, we generated a stable low 4F2hc clear cell RCC cell line (93% downregulation) and compared the protein expression as well as the tumor cell behavior with a high expressing mock transfected counterpart cell line. We found that tumor cell behavior such as cell proliferation, cell survival and cell migration were significantly impaired, whenever 4F2 expression was downregulated. As 4F2 light chain distribution to cell surface is dependent on 4F2hc, leucine amino acid transport in low 4F2hc/Caki2 cells is impaired, as shown by C14-leucine uptake assays. Transfection of silent mutations either lacking integrin interaction site (delta WALLL) or amino acid transport capabilities (Cys109_330Ser) in low4F2/ Caki2 cells revealed a functional relevance of 4F2hc upon tumor cell behavior. From these data we conclude that 4F2 (1) represents a promising new diagnostic marker for RCCs, whereby grade of differentiation correlates with amount of 4F2 expression, and (2) 4F2 might play a functional role in renal cancer cell behavior. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 430. doi:10.1158/1538-7445.AM2011-430
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