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Identification of toll-like receptor 3 as a potential therapeutic target in clear cell renal cell carcinoma.

Clinical cancer research : an official journal of the American Association for Cancer Research 2007 Oct 1; 13(19):5703-9

Link to PubMed abstract

Morikawa T, Sugiyama A, Kume H, Ota S, Kashima T, Tomita K, Kitamura T, Kodama T, Fukayama M, Aburatani H

Authors' Affiliations: Genome Science Division and Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology and Department of Human Pathology, Graduate School of Medicine, The University of Tokyo.

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 IFNalpha 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.

Keywords: renal cell carcinoma