Asian Pacifc Journal of Cancer Prevention, Vol 16, 2015 8405 DOI:http://dx.doi.org/10.7314/APJCP.2015.16.18.8405 STAT3 and STAT4 SNPs and Risk of Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B Asian Pac J Cancer Prev, 16 (18), 8405-8410 Introduction Liver cancers have been considered as the most cancer- related death. Accounting for 85% of all primary liver cancers is hepatocellular carcinoma (HCC) (Perz et al., 2006; Subramaniam et al., 2013). HCC is also the ffth most common malignancy worldwide (Yang and Roberts, 2010; Subramaniam et al., 2013). The occurrence of HCC is often correlated with several risk factors such as chronic alcohol consumption, afatoxin B1 exposure and persistent infection with hepatitis viruses, including hepatitis B virus (HBV) and hepatitis C virus (HCV) (Ramakrishna et al., 2013; Subramaniam et al., 2013). Additionally, host genetic factors such as signal transducer and activator of transcription (STAT) polymorphisms may contribute to the risk of hepatic carcinogenesis, as accumulated evidences reported that STAT polymorphisms were associated with HBV-related HCC progression (Clark et al., 2013; Jiang et al., 2013; Xie et al., 2013; Kim et al., 2015). STAT3, a key molecule of the Janus kinase (JAK)/ STAT signaling pathway, has been shown to play 1 Research Unit of Hepatitis and Liver Cancer, 2 Department of Biochemistry, 3 Department of Radiology, 4 Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand *For correspondence: pisittkvn@yahoo.com Abstract Hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) development. Recent studies demonstrated that single nucleotide polymorphisms (SNPs) rs2293152 in signal transducer and activator of transcription 3 (STAT3) and rs7574865 in signal transducer and activator of transcription 4 (STAT4) are associated with chronic hepatitis B (CHB)-related HCC in the Chinese population. We hypothesized that these polymorphisms might be related to HCC susceptibility in Thai population as well. Study subjects were divided into 3 groups consisting of CHB-related HCC (n=192), CHB without HCC (n=200) and healthy controls (n=190). The studied SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the distribution of different genotypes for both polymorphisms were in Hardy-Weinberg equilibrium (P>0.05). Our data demonstrated positive association of rs7574865 with HCC risk when compared to healthy controls under an additive model (GG versus TT: odds ratio (OR) =2.07, 95% confdence interval (CI)=1.06-4.03, P=0.033). This correlation remained signifcant under allelic and recessive models (OR=1.46, 95% CI=1.09-1.96, P=0.012 and OR=1.71, 95% CI=1.13-2.59, P=0.011, respectively). However, no signifcant association between rs2293152 and HCC development was observed. These data suggest that SNP rs7574865 in STAT4 might contribute to progression to HCC in the Thai population. Keywords: Chronic hepatitis B - hepatocellular carcinoma - STAT3 - STAT4 - single nucleotide polymorphisms RESEARCH ARTICLE Single Nucleotide Polymorphisms in STAT3 and STAT4 and Risk of Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B Nawin Chanthra 1,2 , Sunchai Payungporn 1,2 , Natthaya Chuaypen 1,2 , Kesmanee Piratanantatavorn 2 , Nutcha Pinjaroen 3 , Yong Poovorawan 4 , Pisit Tangkijvanich 1,2 * pivotal role in the transcription of genes important for infammation, survival, proliferation and invasion of HCC (Sansone and Bromberg, 2012; Subramaniam et al., 2013). STAT3 activation is tightly controlled to prevent dysregulation of gene transcription in normal cells, whereas constitutively activated STAT3 plays a crucial role in transcriptional gene involved in oncogenic transformation (Subramaniam et al., 2013). Moreover, STAT3 can be activated by HBV X protein (Lee and Yun, 1998; Wang et al., 2012). The activated STAT3 specifcally binds HBV enhancer 1, leading to stimulation of HBV gene expression (Waris and Siddiqui, 2002; Wang et al., 2009). Results from recent study have demonstrated that single nucleotide polymorphism (SNP) rs2293152 in STAT3 was signifcantly associated with an increased risk of HCC in comparison to the subjects without HCC in Chinese population. The impact of this SNP was greater in women when compared to men (Xie et al., 2013). In addition to STAT3 protein, STAT4 is also a member of STAT family proteins (Subramaniam et al., 2013). STAT4 regulates transcription and expression of various