UBE2L3, a susceptibility gene that plays oncogenic role in hepatitis B-related hepatocellular carcinoma
UBE2L3, a susceptibility gene that plays oncogenic role in hepatitis B-related hepatocellular carcinoma
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UBE2L3，一种易感基因，在乙型肝炎相关肝细胞癌中发挥致癌作用。
DOI：
10.1111/jvh.12963
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发表时间：
2018-11-01
影响因子：
2.5
通讯作者：
Li, Jianming
中科院分区：
文献类型：
--
作者：
Liu, Yao;Song, Ci;Li, Jianming
此前，我们通过全基因组关联研究发现UBE2L3是慢性乙型肝炎病毒（HBV）感染的易感基因。在此，我们分析了UBE2L3基因变异与hbv相关肝细胞癌（HCC）易感性之间的关系，并进一步探讨了其在HCC中的作用。本病例对照研究包括1344名清除HBV的受试者，1560名HBV携带者和1057名HBV相关HCC患者。对2个单核苷酸多态性进行基因分型，分别为rs2266959和rs4821116。采用Logistic回归分析计算优势比（OR）和95%置信区间（CI）。基于癌症基因组图谱（TCGA）数据和我们的组织芯片，我们进一步分析了UBE2L3的表达及其与病理特征的关系。在UBE2L3基因敲低或不敲低的肝癌细胞系中进行增殖和迁移试验。进一步进行RNA-seq分析以探索潜在的致癌机制。UBE2L3中rs4821116的变异基因型与HCC和慢性HBV感染风险降低相关。此外，基于TCGA和我们的组织微阵列数据，较高水平的UBE2L3表达与较高的肿瘤分级、晚期肿瘤分期和较差的生存率相关。体外分析显示UBE2L3可促进肝细胞增殖和迁移。RNA-seq分析显示，UBE2L3与细胞周期负调节因子CDKN2B和CLDN1呈负相关，CLDN1的缺失可能促进癌症转移。综上所述，UBE2L3也可能是hbv相关HCC的易感基因，它可能通过负调控CDKN2B和CLDN1促进HCC的增殖和迁移。
Previously, we identified UBE2L3 as a susceptibility gene for chronic hepatitis B virus (HBV) infection through genome-wide association study. Here, we analysed the association between genetic variants of UBE2L3 and the susceptibility to HBV-related hepatocellular carcinoma (HCC) and further explored its role in HCC. This case-control study included 1344 subjects who cleared HBV, 1560 HBV carriers and 1057 HBV-related HCC patients. Two single nucleotide polymorphisms (SNPs) were genotyped, including rs2266959 and rs4821116. Logistic regression analysis was performed to compute the odds ratio (OR) and 95% confidence interval (CI). We further analysed the expression of UBE2L3 and its association with pathological features based on The Cancer Genome Atlas (TCGA) data and our tissue microarray. Proliferation and migration assays were performed in hepatoma cell lines with or without UBE2L3 knockdown. Further RNA-seq analysis was performed to explore the underlying oncogenic mechanism. The variant genotypes of rs4821116 in UBE2L3 were associated with decreased risk for HCC and chronic HBV infection. Moreover, based on both TCGA and our tissue microarray data, higher levels of UBE2L3 expression were correlated with higher tumour grade, advanced tumour stage and poor survival. In vitro analysis revealed that UBE2L3 may promote hepatocyte proliferation and migration. RNA-seq analysis showed that UBE2L3 was inversely correlated with CDKN2B, a negative regulator of cell cycle, and CLDN1, loss of which may promote cancer metastasis. In conclusion, UBE2L3 may also be a susceptibility gene in HBV-related HCC, and it may promote HCC proliferation and migration by negatively regulating CDKN2B and CLDN1.