Functional variant in the 3'-untranslated region of Toll-like receptor 4 is associated with nasopharyngeal carcinoma risk.
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. Sixty hours 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.
Song
Chang
C
State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University, Cancer Center, Guangzhou, China.
Chen
Li-Zheng
LZ
Zhang
Ru-Hua
RH
Yu
Xing-Juan
XJ
Zeng
Yi-Xin
YX
D020413:3' Untranslated Regions / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D009303:Nasopharyngeal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics*
D020413:3' Untranslated Regions; D017931:DNA Primers; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4