A single nucleotide polymorphism in the 3'-UTR of STAT3 regulates its expression and reduces risk of pancreatic cancer in a Chinese population

Abstract

Pancreatic cancer (PC) is one of the deadliest solid malignancies carrying a gloomy 5-year survival rate less than 5%. The signal transducer and activator of transcription 3 (STAT3) is a common transcriptional regulator, whose aberrant expression has been widely found in human cancers, including PC. Our current study aimed to illustrate the roles of common variants, in the three prime untranslated region (3'UTR) of STAT3, in modifying the risk of PC through two-stage case-control studies integrating biological experiments. We first explored the associations between two common variants (rs1053004 and rs1053005) and PC risk in 774 PC cases and 777 controls. Only rs1053004 T > C showed a significant association with a reduced risk of PC with an odds ratio (OR) and 95% confidence interval (CI) of 0.85 (0.74-0.98). Then we attempted to validate the association in another 940 cases and 1398 controls, and the significant association persisted with OR (95%CI) of 0.86 (0.76-0.97). Dual luciferase reporter gene assays indicated that C allele conferred a higher expression of STAT3 in three PC cell lines including Panc-1 (P = 3.0 × 10-3), BxPC-3 (P = 6.7 × 10-5) and SW1990 (P = 4.0 × 10-3). In conclusion, the current study provided evidence that rs1053004 T > C in 3'UTR of STAT3 may decrease the risk of PC through up-regulating the gene expression.

Keywords: STAT3; case-control study; genetic variants; pancreatic cancer; susceptibility.

Figure 1. Dual luciferase reporter gene assays: the effects of rs1053004 on gene expression

The figure showed that compared to the construct with rs1053004-T, the construct with rs1053004-C had significantly higher luciferase activity in three PC cell lines. Unpaired Student's t-test was used to evaluate the differences and p values less than 0.05 was considered significant with ** indicating p < 0.01 and **** indicating p < 0.001.