Abstract
The purpose of the present study was to assess whether the rs112395617 polymorphism located in the Janus kinase 1 (JAK1) 3' untranslated region (3' UTR) was associated with the risk of hepatocellular carcinoma (HCC), and to explore the potential mechanism of action. Genomic DNA was extracted from peripheral blood of 290 patients with HCC and 320 controls. A polymerase chain reaction-polyacrylamide gel electrophoresis assay was used to genotype the rs112395617 polymorphism. Quantitative (q)PCR was used to detect the genotype-phenotype association between HCC tissues and different genotypes. Vectors containing the insertion (ins)/ins or deletion (del)/del genotype of the rs112395617 polymorphism were constructed, and the luciferase assay was used to detect the JAK1 transcriptional activity affected by the rs112395617 polymorphism. It was identified that, when compared with the ins/ins genotype, the del/del and del/ins genotypes of rs112395617 were significantly associated with a decreased risk of HCC. The qPCR results demonstrated that the JAK1 mRNA expression level with ins/ins and ins/del genotypes was increased by 3.36 and 1.75-fold compared with the del/del genotype in human HCC tissue samples. In addition, the 'AATT' insertion allele of rs112395617 disrupted the binding site for microRNA (miR)-431-5p, thereby increasing JAK1 transcription in vitro. These data suggest that the rs112395617 polymorphism may contribute to HCC susceptibility, in full or at least partially through an effect on JAK1 transcriptional activity by disrupting its binding with miR-431-5p.
Highlights
Hepatocellular carcinoma (HCC) is a common liver cancer and its mortality rate ranks third among cancer‐associated mortalities worldwide in 2008 [1,2]
The association between polymorphisms in the Janus kinase 1 (JAK1) exon and the risk of HCC or other types of cancer has been investigated [10,11,12,13], to the best of our knowledge, no study concerning the effect of polymorphisms in the 3' untranslated region (3' UTR) of JAK1 on HCC has been performed
The present study assessed the effect of the rs112395617 polymorphism in the 3' UTR of JAK1 on the prevalence of HCC, and the potential mechanism of action
Summary
Hepatocellular carcinoma (HCC) is a common liver cancer and its mortality rate ranks third among cancer‐associated mortalities worldwide in 2008 [1,2]. The Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) signal pathway plays a key role in HCC [6]. Murphy et al [7] suggested that interferon‐α (IFN‐α) serves an anti‐cancer role in HCC through the JAK‐STAT signal pathway, and Subramaniam et al [8] identified that that emodin suppressed STAT3 activation by modulating the activation of the upstream kinases, including Janus kinase 1 (JAK1), in HCC. JAK1, located on chromosome 1p31.3, was first identified in 1991 [9] It is a crucial component of diverse signal pathways, and polymorphisms in JAK1 may be functional and serve a role in human cancer development [10,11]. Xie et al [12] demonstrated that mutations in JAK1 may contribute to the development of HCC, and Yang et al [13] revealed that JAK1S703I was an activating mutation for the JAK‐STAT signaling pathway, which may represent a novel therapeutic approach for HCC
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