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Clinical Study
Functional Variant in the 3’-untranslated Region of Toll-Like Receptor 4 is Associated with Nasopharyngeal Carcinoma Risk
Chang Song, Li-Zheng Chen, Ru-Hua Zhang, Xing-Juan Yu and Yi-Xin Zeng
volume 5 | issue 10
october 2006Pages: 1285 - 1291
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Signaling pathways activated by the Toll-like receptor 4 (TLR4) involve the induction of anti-cancer immunity. While screening for nasopharyngeal carcinoma (NPC) susceptibility genes, we isolated TLR4 and found that the 3'-untranslated region (3'-UTR) of exon 4 contained two polymorphisms that may alter its translation efficiency, potentially leading to NPC. To test this hypothesis, we conducted a hospital-based case-controlled study on NPC patients and cancer-free controls. We determined that the variant allele 11350C and the 11350GC genotype were associated with a significantly increased risk for NPC. We also determined significant differences between the male gender group and the remaining patient cases and controls, and between subjects equal to or younger than 47 years old and the cases and controls. Secondly, we cloned the entire 3’-UTR into a luciferase reporter system, and compared the luciferase activities between the wild-type 3’-UTR construct (WILD) and a construct containing the 11350C variant (MUT). Both constructs caused lower reporter gene activities, as compared to the positive control pGL3-promoter plasmid. 60 h after the transfections, the MUT construct reduced the reporter gene activity by 40% compared to that of the WILD construct (P < 0.05). Functional analyses of the 11350C variant suggested that the TLR4 3’-UTR is a potent regulator of gene expression, as the mutated TLR4 3’-UTR was associated with decreased mRNA stability, and may down-regulate TLR4 expression resulting in EBV metainfective antiviral immunologic deficits and a high risk of NPC.
Authors
Chang Song
Sun Yat-sen University, Cancer Center, Guangzhou, China
Li-Zheng Chen
Sun Yat-sen University, Cancer Center, Guangzhou, China
Ru-Hua Zhang
Sun Yat-sen University, Cancer Center, Guangzhou, China
Xing-Juan Yu
Sun Yat-sen University, Cancer Center, Guangzhou, China
Yi-Xin Zeng
State Key Laboratory of Oncology in South China; and Sun Yat-sen University Cancer Center
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.