Kuan-Chun Hsueh, Yi-Hsien Hsieh, Shih-Chi Su, Edie-Rosmin Wu, Lun-Ching Chang, Shun-Fa Yang, Hsiang-Lin Lee
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While assessing the clinicopathological parameters, we demonstrated that patients carrying at least one minor allele of rs6478108 (T) or rs6478109 (G) were less prone to develop distant metastasis (rs6478108, TC + TT vs. CC, OR, 0.414; 95% CI, 0.185-0.924, p = 0.027) (rs6478109, GA + GG vs. AA, OR, 0.397; 95% CI, 0.178-0.888; p = 0.021) as compared with patients who are homozygous for the major allele. In addition, preliminary exploration of public datasets exhibited that rs6478108 and rs6478109 affected TNFSF15 gene expression to various degrees in the liver tissues and whole blood samples. Moreover, gene silencing experiments revealed that elevated TNFSF15 levels are essential for promoting cell migration in HCC. 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引用次数: 0
摘要
肝细胞癌(HCC)病因复杂,涉及遗传因素,是全球公共卫生负担。肿瘤坏死因子超家族成员15 (TNFSF15)是一种T淋巴细胞共刺激细胞因子,已知可调节血管生成和炎症,暗示其在癌症发展中的潜在作用。在本研究中,我们试图探讨TNFSF15基因变异对HCC发病风险的影响。共纳入408例HCC患者和1190例非癌对照,采用TaqMan等位基因鉴别法分析TNFSF15基因(rs3810936、rs6478108和rs6478109)的等位基因分布。在对假定的混杂因素进行校正后,这三个snp均与HCC的发生无关。在评估临床病理参数时,我们发现携带至少一个rs6478108 (T)或rs6478109 (G)小等位基因的患者发生远处转移的可能性较小(rs6478108, TC + TT vs. CC, or, 0.414;95% CI, 0.185-0.924, p = 0.027) (rs6478109, GA + GG vs. AA, OR, 0.397;95% ci, 0.178-0.888;P = 0.021),与主等位基因纯合的患者相比。此外,对公开数据集的初步探索显示,rs6478108和rs6478109在肝组织和全血样本中不同程度地影响TNFSF15基因的表达。此外,基因沉默实验显示,升高的TNFSF15水平对于促进HCC中的细胞迁移至关重要。我们的研究结果表明,TNFSF15基因多态性与HCC转移潜力存在性别特异性关联。
Potential Influence of TNFSF15 Genetic Variants and Expression Levels on Disease Progression in Patients With Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC), whose complex etiology involves a genetic component, is a global public health burden. Tumor necrosis factor superfamily member 15 (TNFSF15) is a T lymphocyte-costimulatory cytokine known to modulate angiogenesis and inflammation, implicating its potential role in cancer development. In this study, we attempted to explore the influence of TNFSF15 gene variations on the risk for HCC. In total, 408 HCC patients and 1190 noncancer controls were enrolled, and allelic distributions of TNFSF15 gene (rs3810936, rs6478108, and rs6478109) were analyzed using a TaqMan allelic discrimination assay. After adjustment for the putative confounding factors, none of these three SNPs was associated with the development of HCC. While assessing the clinicopathological parameters, we demonstrated that patients carrying at least one minor allele of rs6478108 (T) or rs6478109 (G) were less prone to develop distant metastasis (rs6478108, TC + TT vs. CC, OR, 0.414; 95% CI, 0.185-0.924, p = 0.027) (rs6478109, GA + GG vs. AA, OR, 0.397; 95% CI, 0.178-0.888; p = 0.021) as compared with patients who are homozygous for the major allele. In addition, preliminary exploration of public datasets exhibited that rs6478108 and rs6478109 affected TNFSF15 gene expression to various degrees in the liver tissues and whole blood samples. Moreover, gene silencing experiments revealed that elevated TNFSF15 levels are essential for promoting cell migration in HCC. Our results indicate gender-specific association of TNFSF15 gene polymorphisms with the metastatic potential of HCC.
期刊介绍:
Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.