A single nucleotide polymorphism in microRNA-146a is associated with the risk for nasopharyngeal carcinoma.
A common GC polymorphism within miRNA-146a precursor region (rs2910164) has been associated with the risk of various cancers despite the underlying mechanism is unclear. In the current study, we aimed to examine the role of rs2910164 in the pathogenesis and predisposition to nasopharyngeal carcinoma (NPC). The GC polymorphism in 233 NPC patients, 173 matched controls and 3613 healthy elderly subjects in our locality were first determined using melting temperature (T(m))-shift allele-specific genotyping method. Results in our case-control study indicated that CC genotype was associated with the risk effect of NPC (adjusted odds ratio of GC + GG vs. CC, 0.49; 95% confidence interval, 0.35-0.69; P < 0.0001). Using real-time polymerase chain reaction (PCR) assay, we subsequently revealed that expressions of both miR-146a and its passenger strand (miR-146a*C or miR-146a*G) were increased in NPC samples (P < 0.001), albeit expression of miR-146a was not linked to the genotype. Furthermore, miR-146a*C in NPC was significantly increased in CC genotype (CC vs. GC, P = 0.038). Finally, we demonstrated by co-immunoprecipitation and luciferase reporter assays that all three miR-146a precursor-derived mature miRNAs interacted with Argonaute2 (Ago2) protein complex and could function as gene silencers. Taken together, our results showed that the variant C in rs2910164 was associated with the predisposition of NPC in Chinese population. This polymorphism may influence the risk of NPC by producing active mature miR-146a*C that regulate distinct set of target genes. These findings may enrich our understanding of how miRNA single nucleotide polymorphism affect NPC pathogenesis, and may have potential implications to improve NPC treatment in the future.
Department of Anatomical and Cellular Pathology at Li Ka-Shing Institute of Health Sciences, Sir Y.K. Pao Center for Cancer, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR, China.
Raymond Wai-Ming
RW
Lung
Xingyan
X
Wang
Joanna Hung-Man
JH
Tong
Shuk-Ling
SL
Chau
Kin-Mang
KM
Lau
Shuk-Hang
SH
Cheng
John Kong-Sang
JK
Woo
Jean
J
Woo
Ping-Chung
PC
Leung
Margaret Heung-Ling
MH
Ng
Nelson Leung-Sang
NL
Tang
Ka-Fai
KF
To
D000368:Aged; D060565:Argonaute Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000209:etiology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors
C466422:AGO2 protein, human; D060565:Argonaute Proteins; D014408:Biomarkers, Tumor; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D008156:Luciferases