Abstract
We examined whether genetic polymorphisms of efflux transporters in hepatocytes are associated with susceptibility to develop hepatocellular carcinoma (HCC). Genetic polymorphisms of drug transporters expressed in hepatocytes were analyzed using DNA samples from hepatitis C virus (HCV)-seropositive cirrhotic patients with HCC (n = 58), and allele and haplotype frequencies were compared with those in healthy subjects (n = 61). To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 34 SNPs in 6 efflux transporters [MDR1 (ABCB1), ABCC1, ABCC2, ABCC3, ABCG2 and ABCB11] were determined. No significant association was observed for any single SNP; however, some haplotypes in ABCC1 and ABCB11 were associated with HCC. Furthermore, three combinations of SNPs (3435C > T in ABCB1 and 825T > C in ABCC1), (3435C > T in ABCB1 and -15281_-15278CTCT > delete in ABCB11), and (825T > C in ABCC1 and -15281_-15278CTCT > delete in ABCB11) were significantly associated with HCC. The present study suggests that genetic variations of ABC transporters such as ABCB1, ABCB11, and ABCC1 are associated with susceptibility to develop HCC, implying that aberrant hepatic clearance of toxic substances may increase the risk of hepatocarcinogenesis. Further studies of how these polymor-phisms are associated with phenotypic differences are warranted.
Highlights
Hepatocellular carcinoma (HCC) is a frequent complication in advanced chronic liver disease, and is a major cause of death worldwide
We examined whether genetic polymorphisms of efflux transporters in hepatocytes are associated with susceptibility to develop hepatocellular carcinoma (HCC)
The present study suggests that genetic variations of ABC transporters such as ABCB1, ABCB11, and ABCC1 are associated with susceptibility to develop HCC, implying that aberrant hepatic clearance of toxic substances may increase the risk of hepatocarcinogenesis
Summary
Hepatocellular carcinoma (HCC) is a frequent complication in advanced chronic liver disease, and is a major cause of death worldwide. In Japan, the high prevalence of HCC has largely been attributed to chronic infection by hepatitis virus, especially hepatitis C virus (HCV) [1,2,3]. HCV infection with persistent inflammation leads to sequential progression from acute to chronic hepatitis, cirrhosis, and eventually HCC in some cases. One important protective function of the liver is the biliary and sinusoidal clearance of such endogenous and exogenous mutagenic/carcinogenic substances, preventing their accumulation in hepatocytes. This function is maintained by a drug efflux transporter system that comprises mainly the ABC-transporter proteins [5,6]. Mutation(s) of these proteins may impair the protective system against accumulation of hazardous compounds that may lead to HCC
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