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.