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


METHODS
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.
Morikawa
Teppei
T
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Japan.
Sugiyama
Akira
A
Kume
Haruki
H
Ota
Satoshi
S
Kashima
Takeshi
T
Tomita
Kyoichi
K
Kitamura
Tadaichi
T
Kodama
Tatsuhiko
T
Fukayama
Masashi
M
Aburatani
Hiroyuki
H
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011070:Poly I-C / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D007369:Interferon Inducers; D051196:Toll-Like Receptor 3; D011070:Poly I-C