Wang Chaoqun, Zhao Hua, Zhao Xiankun, Wan Jiao, Wang Dayong, Bi Wanli, Jiang Xinghong, Gao Yuzhen
Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China.
Tumour Biol. 2014 Jan;35(1):295-301. doi: 10.1007/s13277-013-1039-x. Epub 2013 Aug 6.
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, and multiple host genetic factors are believed to contribute to HCC development. The small G protein signaling modulator 3 (SGSM3) has been shown to be associated with small G protein coupled receptor signal transduction pathway, suggesting a potential role in HCC susceptibility. We carried out a case-control study in a Chinese population (502 cases and 513 controls) to determine whether the 4-bp insertion/deletion polymorphism (rs56228771) in 3' untranslated region of SGSM3 could affect HCC susceptibility. Logistic regression analysis showed that compared with the del/del genotype, the ins/del genotype of rs56228771 was associated with a significantly decreased risk of HCC [adjusted odd ratio = 0.55, 95% confidence interval (CI) = 0.42-0.73, P = 1.93 × 10(-5)]. The combined ins/del + ins/ins genotypes contributed to a 45% decreased HCC risk (95% CI = 0.42-0.73, P = 1.03 × 10(-5)). This protective trend was more prominent in the HBsAg-negative subgroup. Furthermore, in vivo experiments showed that mRNA levels of SGSM3 from HCC tumor tissues and adjacent non-HCC tissues were correlated with rs56228771 genotypes. Tissue samples with ins/ins genotype have the highest level of SGSM3, which are 2.85-3.00-fold and 1.46-1.57-fold higher than that with ins/del and del/del genotype, respectively. Similar results were also observed with four common hepatoma cell lines in vitro. In addition, compared with HCC tissues, significantly higher SGSM3 expression was observed in adjacent non-HCC tissues (fold change = 2.48), implying its tumor suppressor roles in HCC. Bioinformatics prediction showed that the insertion allele disrupted a binding site for microRNA (miRNA)-151-5p, which would upregulate SGSM3. Taken together, we provided initial evidence that rs56228771 may contribute to hepatocarcinogenesis, possibly by affecting SGSM3 expression through a miRNA-mediated regulation. The replication of our studies in other populations and functional analysis will further strengthen the underlining mechanism.
肝细胞癌（HCC）是最常见的原发性肝脏恶性肿瘤，多种宿主遗传因素被认为与HCC的发生发展有关。小G蛋白信号调节剂3（SGSM3）已被证明与小G蛋白偶联受体信号转导途径相关，提示其在HCC易感性中可能发挥作用。我们在中国人群（502例病例和513例对照）中开展了一项病例对照研究，以确定SGSM3 3'非翻译区的4碱基插入/缺失多态性（rs56228771）是否会影响HCC易感性。逻辑回归分析显示，与del/del基因型相比，rs56228771的ins/del基因型与HCC风险显著降低相关[校正比值比=0.55，95%置信区间（CI）=0.42-0.73，P=1.93×10⁻⁵]。ins/del+ins/ins基因型组合使HCC风险降低了45%（95%CI=0.42-0.73，P=1.03×10⁻⁵）。这种保护趋势在HBsAg阴性亚组中更为明显。此外，体内实验表明，HCC肿瘤组织和相邻非HCC组织中SGSM3的mRNA水平与rs56228771基因型相关。具有ins/ins基因型的组织样本中SGSM3水平最高，分别比具有ins/del和del/del基因型的样本高2.85-3.00倍和1.46-1.57倍。在四种常见肝癌细胞系的体外实验中也观察到了类似结果。此外，与HCC组织相比，在相邻非HCC组织中观察到SGSM3表达显著更高（变化倍数=2.48），这意味着其在HCC中具有肿瘤抑制作用。生物信息学预测表明，插入等位基因破坏了微小RNA（miRNA）-151-5p的一个结合位点，这将上调SGSM3。综上所述，我们提供了初步证据表明rs56228771可能通过miRNA介导的调控影响SGSM3表达，从而参与肝癌发生。在其他人群中重复我们的研究并进行功能分析将进一步强化潜在机制。
