Association of Single Nucleotide Polymorphism rs1053004 in Signal Transducer and Activator of Transcription 3 (STAT3) with Susceptibility to Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B.

Nawin Chanthra,Pisit Tangkijvanich,Nutcha Pinjaroen,Yong Poovorawan,Natthaya Chuaypen,Sunchai Payungporn

doi:10.7314/apjcp.2015.16.12.5069

Abstract

The single nucleotide polymorphism (SNP) rs1053004 in Signal transducer and activator of transcription 3 (STAT3) was recently reported to be associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) in a Chinese cohort. This study was aimed at investigating whether the SNP might also contribute to HCC susceptibility in the Thai population. Study subjects were enrolled and divided into 3 groups including CHB-related HCC (n=211), CHB without HCC (n=233) and healthy controls (n=206). The SNP was genotyped using allelic discrimination assays based on TaqMan real-time PCR. Data analysis revealed that the distribution of different genotypes was in Hardy-Weinberg equilibrium (P>0.05). The frequencies of allele T (major allele) in HCC patients, CHB patients and healthy controls were 51.4%, 58.6% and 61.4%, respectively, whereas the frequencies of C allele (minor allele) were 48.6%, 41.4% and 38.6%. The C allele frequency was higher in HCC when compared with CHB patients (odds ratio (OR)=1.34, 95% confidence interval (CI)=1.02-1.74, P=0.032). The genotype of SNP rs1053004 (CC versus TT+TC) was significantly associated with an increased risk when compared with CHB patients (OR=1.83, 95% CI=1.13-2.99, P=0.015). In addition, we observed a similar trend of association when comparing HCC patients with healthy controls (OR=1.77, 95% CI=1.07-2.93, P=0.025) and all controls (OR=1.81, 95% CI=1.19-2.74, P=0.005). These findings suggest that the SNP rs1053004 in STAT3 might contribute to HCC susceptibility and could be used as a genetic marker for HCC in the Thai population.

Highlights

Signal transducer and activator of transcription (STAT) proteins are inflammatory mediators which transduce signal across the cytoplasm and function as transcription factors in the nucleus (Yu et al, 2009)
We found that there was no significant difference in age and gender distribution between hepatocellular carcinoma (HCC) and chronic hepatitis B (CHB) patients (P=0.091 and 0.409, respectively) and we observed the same trend in HBV DNA levels (P=0.689)
Constitutively activated Signal transducer and activator of transcription 3 (STAT3) is crucial for compensating hepatocyte turnover and leads to advanced fibrosis and cirrhosis, which are the key clinical risk factors for HCC development (Subramaniam et al, 2013)

Summary

Introduction

Signal transducer and activator of transcription (STAT) proteins are inflammatory mediators which transduce signal across the cytoplasm and function as transcription factors in the nucleus (Yu et al, 2009). Activations of the STAT proteins through growth factors and cytokine receptors have been implicated in initiation and progression of cancer (Yu and Jove, 2004; Yu et al, 2009). The STAT protein family comprises seven members, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 (Yu and Jove, 2004; Subramaniam et al, 2013). Among STAT family protein, the STAT3 has gained a considerable attention because it relates to hepatocarcinogenesis, by which regulates numerous genes involved in many biological and cellular processes, including survival, angiogenesis, proliferation and inflammation of the hepatocytes (Subramaniam et al, 2013). Previous studies indicated that STAT3 can be activated by the X protein of HBV and activated STAT3 can bind with the HBV enhancer 1 to activate gene expression, suggesting the interplay between STAT3 and X protein in promoting HCC development (Waris and Siddiqui, 2002)

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