Abstract
The interleukin- (IL-) 33/ST2 axis plays a pivotal role in tumorigenesis through influencing cancer stemness and other mechanisms. CD44 is one of the critical markers of hepatocellular carcinoma (HCC) among the cancer stem cells (CSCs). There is still a lack of CD44 gene single-nucleotide polymorphisms (SNPs) combined with IL-33/ST2 pathway single-nucleotide polymorphisms in HCC susceptibility analysis literature, although CD44 and IL-33/ST2 have been reported separately in human cancers. This study is aimed at investigating the relationship between CD44, IL-33, and ST2 SNPs and HCC susceptibility and clinicopathological features. We analyzed 565 HCC patients and 561 healthy controls in the Chinese population. The genes for CD44rs187115A>G, IL-33 rs1929992A>G, and ST2 rs3821204G>C were typed using the SNaPshot method. We found that the distribution frequencies of CD44 and ST2 alleles and genotypes in both the HCC case group and the control group were statistically significant (p < 0.05). The results showed that individuals carrying at least one G allele of the CD44 rs187115 gene were at a higher risk than the AA genotype carriers (p = 0.007, odds ratio (OR) = 1.429, 95% confidence interval (CI): 1.102–1.854). Similarly, individuals with at least one C allele of ST2 rs3821204 had a higher risk of HCC than those with GG genes (p ≤ 0.001, OR = 1.647, 95% CI: 1.296-2.093). Combining the haplotype analysis of the 3 loci suggested that CD44 rs187115, IL-33 rs1929992, and ST2 rs3821204 are associated with the risk of HCC and could potentially serve as useful genetic markers for HCC in some populations of China.
Highlights
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide
We further studied the clinical status of CD44 rs187115 gene polymorphism in HCC to assess whether there was a difference in the distribution of the rs187115 genotype among clinical subgroups
We further explored biological effects of the three significant single-nucleotide polymorphisms (SNPs) (CD44 rs187115, IL-33 rs1929992, and ST2 rs3821204) on their gene expression by investigating a public database (GTEx portal).We found that genotypes of these SNPs were not associated with their gene expression in liver tissue and whole blood cells
Summary
The annual global incidence of primary liver cancer is 841,000; the death rate is 782,000; and it is the second highest mortality rate among males [1]. The mortality rate of liver cancer in China is the second highest among malignant tumors (new liver cancer accounts for more than 50% of the world’s total) and is following a trend of annual increase [2]. Liver transplantation, and tumor ablation are the potential curative therapies; these treatment options are only applicable to patients in the early stage of disease [3, 4]. Due to the highly malignant potential of HCC, diagnosis is not usually made until an advanced stage, at which point there are no effective therapies to be offered [5]. Single-nucleotide polymorphism (SNP), a well-defined molecular biomarker, has been widely applied in HCC susceptibility evaluation [6, 7]
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