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Identification of Toll-Like Receptor 3 as a Potential Therapeutic Target in Clear Cell Renal Cell Carcinoma

Authors' Affiliations: ¹ Genome Science Division and ² Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology and ³ Department of Human Pathology, Graduate School of Medicine, The University of Tokyo; ⁴ Department of Urology, The University of Tokyo Hospital; and ⁵ Perseus Proteomics, Inc., Tokyo, Japan

Requests for reprints: Hiroyuki Aburatani, Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan. Phone: 81-3-5452-5352; Fax: 81-3-5452-5355; E-mail: haburata-tky{at}umin.ac.jp.

Purpose: Renal cell carcinoma (RCC) is one of the most drug-refractory cancers. The aim of this study is to discover a novel therapeutic target molecule for clear cell RCC (CCRCC), which accounts for the majority of RCC.

Experimental Design: Gene expression profiles of 27 CCRCCs and 9 normal kidney tissues as well as 15 various adult normal tissues were examined by Affymetrix U133 Plus 2.0 arrays. Among the 34 genes specifically up-regulated in CCRCC, overexpression of Toll-like receptor 3 (TLR3) mRNA and its protein was validated by quantitative reverse transcription-PCR, immunoblot, and immunohistochemistry. The effects of TLR3 signaling on in vitro cell growth were examined.

Results: TLR3 gene was highly expressed in CCRCC, with only limited expression in a panel of normal tissues. On immunohistochemical analysis using a monoclonal antibody against TLR3, overexpression of TLR3 was observed in 139 of 189 (73.5%) cases of CCRCC as well as in lung metastatic CCRCC (6 of 8), whereas TLR3 expression was entirely absent in chromophobe RCC (0 of 8). Polyinosinic-polycytidilic acid, a TLR3 ligand, exerted a growth-inhibitory effect against RCC cells in a TLR3-dependent manner. Moreover, a combination of polyinosinic-polycytidilic acid and IFN exerted a synergistic growth-inhibitory effect against Caki-1 RCC cells.

Conclusions: This is the first report that TLR3 is overexpressed in CCRCC. These observations suggest that TLR3 pathway may represent a novel therapeutic target in CCRCC.

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