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.
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.
Authors: Han W Tun; Laura A Marlow; Christina A von Roemeling; Simon J Cooper; Pamela Kreinest; Kevin Wu; Bruce A Luxon; Mala Sinha; Panos Z Anastasiadis; John A Copland Journal: PLoS One Date: 2010-05-18 Impact factor: 3.240
Authors: M Murohashi; K Hinohara; M Kuroda; T Isagawa; S Tsuji; S Kobayashi; K Umezawa; A Tojo; H Aburatani; N Gotoh Journal: Br J Cancer Date: 2009-12-08 Impact factor: 7.640
Authors: Yasufumi Goto; Takaaki Arigami; Minoru Kitago; Sandy L Nguyen; Norihiko Narita; Soldano Ferrone; Donald L Morton; Reiko F Irie; Dave S B Hoon Journal: Mol Cancer Ther Date: 2008-11 Impact factor: 6.261