| The microRNA (miRNA) biogenesis genes involve in the sequential processing ofmiRNA: the generation of pre-miRNA from pri-miRNA by the Drosha/DGCR8complex in the nucleus, and the generation of mature miRNAs from pre-miRNAs by theDicer/TRBP complex in the cytoplasm. Sequence variations (e.g. single nucleotidepolymorphisms, SNPs) within the miRNA biogenesis genes may have profound affectson miRNA biogenesis and function. Several studies have demonstrated that miRNAbiogenesis genes participate in the pathogenesis of common diseases, including cancers.Also, miRNA biogenesis genes polymorphisms were shown to be associated withseveral kinds of cancers. The role of the miRNA biogenesis genes polymorphisms innasopharyngeal carcinoma (NPC) and hepatocellular carcinoma (HCC), however, hasnever been specifically investigated. In the present study, we examined whether theSNPs within microRNA biogenesis genes have any bearing on the susceptibility to andseverity of NPC and HCC, respectively. The main results are as follows:1. The genetic associations between miRNA biogenesis gene polymorphisms andsusceptibility to and severity of NPCNinety-seven SNPs were first genotyped in a case-control population fromGuangxi province (855cases and1036controls), then the significantly associated SNPswere further genotyped in another case-control population from Guangdong province(997cases and972controls) and222nuclear families. We observed that a SNP,rs3928672in AGO2, was significantly associated with both susceptibility to and lymphnode metastasis of NPC. Compared with the GG genotype carriers, the GA and AAgenotype carriers had a significantly increased risk of the occurrence of NPC (OR=1.20,95%CI=1.05-1.36, P=0.006), and a significantly increased lymph node metastasis(OR=1.97,95%CI=1.37-2.83, P=0.003). Linkage disequilibrium (LD) analysis showed that rs3928672is not in strong LD with all the other SNPs within AGO2gene.Furthermore, stratified analysis indicated that the increased susceptibility to NPCrelated to the rs3928672genotypes was more pronounced in heavier smokers. Finally,bioinformatics analysis indicated that the rs3928672may change the transcriptionalactivity.We futher explored the function of AGO2gene. We investigated the proteinexpression of AGO2in NPC patients and controls by immunohistochemistry (IHC). Wedetected significantly increased expression of AGO2in NPC tissues than in normalnasopharyngeal tissues. Also, the expression of AGO2was greater in NPC patients withadvanced N staging. By knocking-down of AGO2, the migration of CNE2Z cell linewas significantly inhibited. After knocking-down of AGO2, the mRNA and miRNAexpression profiles of CNE2Z were significantly changed, and, the signal pathways andcatalogues related to the proliferation and metastasis of cancers, including ‘RAS’,‘ERK’,‘MAPK’ and ‘Invasion’ were significantly enriched. Taken together, ourfindings suggest that the genetic polymorphism in AGO2may play a role in mediatingsusceptibility to and severity of NPC in Chinese population.2. The genetic associations between miRNA biogenesis gene polymorphisms andsusceptibility to HBV-related HCC.We selectd178SNPs within miRNA biogenesis genes, and genotyped these SNPsin a case-control population from Guangxi province (358patients with HCC and373controls).We observed that the PACT rs3752689(OR=1.42,95%CI=1.11-1.81,P=0.006), IPO8rs6487924(OR=1.60,95%CI=1.09-2.37, P=0.002) and AGO2rs938726(OR=2.26,95%CI=1.41-3.61, P=0.0003) were significantly associated withthe risk of HBV-related HCC. The IPO8rs6487924was further confirmed in anothercase-control population from Guangdong (751cases and509controls), with the ORbeing1.49(95%CI=1.08-2.07, P=0.010). Taken together, our findings suggest that thegenetic polymorphisms in PACT, IPO8and AGO2may play roles in mediatingsusceptibility to HBV-related HCC in Chinese population. |
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