Potential Influence of NUCB2 Genetic Variants on the Clinicopathological Features of Patients with Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most commonly diagnosed cancer type worldwide in males and the ninth among females, and it is a primary cause of cancer-associated death. The adipokine nesfatin-1, initially discovered in hypothalamic neurons, is produced by the precursor NUCB2 gene. The relationship between NUCB2 polymorphisms, behavioral risk factors that facilitate cancer, and HCC is still unknown. Methods: Four NUCB2 genetic polymorphisms were investigated in 822 normal controls and 411 patients with HCC using qPCR. The GTEx portal was used to assess the association between NUCB2 genetic variants and expression. NUCB2 levels in patients with HCC were evaluated using TCGA data. Results: Relative to the wild-type GG genotype, the AA genotype at the NUCB2 SNP rs214101 was associated with an augmented risk of distant metastasis and vascular invasion. The GA and AA genotypes at rs214101 were also associated with an increased likelihood of vascular invasion among smoking HCC patients compared to those carrying the GG genotype. Notably, GTEx data uncovered that the AA homozygous genotype was correlated with remarkably higher NUCB2 levels than those observed in individuals with the rs214101 GG genotype in lymphocytes and whole blood samples. TCGA data revealed that HCC patients exhibited higher NUCB2 expression in tumorous compared to non-tumorous liver tissue. Conclusions: NUCB2 SNP rs214101 may be associated with HCC progression and metastasis.