Novel F141L Pre-S2 Mutation in Hepatitis B Virus Increases the Risk of Hepatocellular Carcinoma in Patients with Chronic Genotype C Infections

Abstract

Several lines of evidence have suggested that some naturally occurring mutations of hepatitis B virus (HBV) play a critical role in hepatocellular carcinoma (HCC). Here, we describe a novel HCC-related pre-S2 mutation, F141L. To prove the relationship between the F141L mutation and HCC, molecular epidemiology studies using MboII PCR restriction analysis (PRA) were performed, and the molecular mechanism was investigated through construction of a stable hepatocyte cell line expressing the large surface HB protein (LHB) with the F141L mutation (F141L-LHB). Application of MboII PRA to samples from 241 Korean patients with chronic liver diseases of different clinical stages confirmed that F141L mutants were significantly related to HCC, even in comparison to liver cirrhosis (HCC, 26.3% of patients, or 26/99; liver cirrhosis, 3.8% of patients, or 2/52; P ‫؍‬ 0.001). By studying stable cell lines, we found that F141L-LHBs could induce cell cycle progression by downregulating the p53 and p21 pathways and upregulating CDK4 and cyclin A. Furthermore, we found that in a colony-forming assay, the colony-forming rates in cell lines expressing F141L-LHBs were about twice as high as those of the wild type. In conclusion, our results suggest that F141L-LHBs may contribute importantly to the pathogenesis of HCC by inducing cell proliferation and transformation. So, the F141L mutation examined in this study could serve as a diagnostic marker for the prognosis of HCC.Hepatitis B virus (HBV) infection is a global health problem. Roughly 2 billion people, one-third of the world's population, have serological evidence of infection. Worldwide, the 350 million people with chronic HBV infection have a 15% to 25% risk of dying from HBV-related liver disease, including end-stage cirrhosis and hepatocellular carcinoma (HCC). Each year, acute and chronic HBV infections cause roughly 1 million deaths (12). Although most carriers will not develop hepatic complications from chronic hepatitis B, 15% to 40% will develop serious sequelae during their lifetimes (17).The clinical expression of hepatitis B in different parts of the world depends not only on the prevalent genotypes but also on the prevalent modes of transmission. In Western countries, HBV infection is relatively rare and is acquired primarily in adulthood, with a low rate of progression to chronicity, rarely, if ever, leading to HCC, whereas in Asia and most of Africa, chronic HBV infection is common and usually acquired perinatally or in childhood and is associated with a high rate of progression to cirrhosis and cancer. The difference in the natural course of infection is mediated by the interaction between virus and host, which is largely determined by the age at which the infection is acquired (18).South Korea is recognized and an area of endemicity for of HBV infection, and based on the Korean National Health and Nutrition Survey of 1998, the prevalence of hepatitis B surface antigen (HBsAg) was 5.1% in men and 4.1% in women (4). Moreover, it was reported that the extraordinary ...

Nucleos(t)ide analogues to treat hepatitis B virus-related hepatocellular carcinoma after radical resection

“…However, the other RCT [38] in our review found that NA therapy significantly decreased early HCC recurrence, while it did not report outcomes on late HCC recurrence. NA therapy may inhibit early HCC recurrence, which usually arises due to diffusion of the primary tumor, by reducing high HBV load and HBV mutations, all of which are associated with HCC metastasis and growth [40][41][42] , as well as by inhibiting HBxAg, which promotes HCC invasiveness and metastatic potential [43,44] . Further studies are urgently needed to clarify whether and how NA therapy affects risk of HCC recurrence, since the results of RCT [38] in our review may overestimate the NA efficacy because the control group at baseline had significantly higher rates of cirrhosis, lower rates of tumor encapsulation, and higher rates of HBeAg positivity than the NA group, as well as poorer tumor differentiation and higher AFP levels.…”

Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis

“…The HBV large envelope protein gene fragment (preS1/ preS2/S), with F141L mutation in the preS2 region, can significantly promote the proliferation of hepatocytes by downregulating the p53 and p21 pathways and upregulating the expression of cyclin-dependent kinase 4 and cyclin A. The colony-forming rates of hepatocytes expressing F141L-large envelope protein are about twice as high as those expressing the wild-type HBV large envelope protein [58] . Random integration of HBV DNA into the host genome is present in HBVinfected subjects.…”

Genetic Factors, Viral Infection, Other Factors and Liver Cancer: An Update on Current Progress

“…Furthermore, the result of bimolecular assays suggested that substitutions and deletion of nucleotides of HBV genome, including G1317A, T1341 C/A/G and pre-S2 deletion may lead to elevated risk of developing hepatocelluar carcinoma, on the other hand, those mutations may capable of serving as the predictor of liver cancer among patients with genotype C chronic hepatitis (Zhang et al, 2007). The latest approach by using Mboll PCR restriction analysis also identified a novel mutation in pre-S2, it is reported that F141L mutation was significantly related to HCC, even in comparison to live cirrhosis among 241 Korean patients (Mun et al, 2011). As for pre-S deletion, it was (Gao et al, 2007) reported that these mutations were more commonly found in the patients with HCC that in the chronic hepatitis B or asymptomatic carrier, suggesting pre-S deletion might involved in HBV-related hepatocarinogenesis.…”