| Summary: | Hepatocellular carcinoma (HCC) often develops from chronic hepatitis B (CHB) through replication of hepatitis B virus (HBV) infection. Calcium (Ca<sup>2+</sup>) signaling plays an essential role in HBV replication. Store-operated calcium (SOC) channels are a major pathway of Ca<sup>2+</sup> entry into non-excitable cells such as immune cells and cancer cells. The basic components of SOC signaling include the <i>STIM1</i> and <i>ORAI1</i> genes. However, the roles of <i>STIM1</i> and <i>ORAI1</i> in HBV-mediated HCC are still unclear. Thus, long-term follow-up of HBV cohort was carried out in this study. This study recruited 3631 patients with chronic hepatitis (345 patients with HCC, 3286 patients without HCC) in a Taiwanese population. Genetic variants of the <i>STIM1</i> and <i>ORAI1</i> genes were detected using an Axiom CHB1 genome-wide array. Clinical associations of 40 polymorphisms were analyzed. Three of the <i>STIM1</i> single-nucleotide polymorphisms (SNPs) (rs6578418, rs7116520, and rs11030472) and one SNP of <i>ORAI1</i> (rs6486795) showed a trend of being associated with HCC disease (<i>p</i> < 0.05). However, after correction for multiple testing, none of the SNPs reached a significant level (<i>q</i> > 0.05); in contrast, neither <i>STIM1</i> nor <i>ORAI1</i> showed a significant association with HCC progression in CHB patients. Functional studies by both total internal reflection fluorescence images and transwell migration assay indicated the critical roles of SOC-mediated signaling in HCC migration. In conclusion, we reported a weak correlation between <i>STIM1/ORAI1</i> polymorphisms and the risk of HCC progression in CHB patients.
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