Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.

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P0531 : Transgenic mice carrying hepatitis B virus pre-S/S gene containing the rtA181T/sW172* mutation develop hepatocellular carcinoma

Journal of Hepatology ◽

10.1016/s0168-8278(15)30739-x ◽

2015 ◽

Vol 62 ◽

pp. S514-S515

Author(s):

C.-T. Yeh ◽

M.-W. Lai ◽

K.-H. Liang ◽

Y.-H. Huang

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

S Gene ◽

B Virus

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Molecular mechanisms of gender disparity in hepatitis B virus-associated hepatocellular carcinoma

World Journal of Gastroenterology ◽

10.3748/wjg.v20.i20.6252 ◽

2014 ◽

Vol 20 (20) ◽

pp. 6252 ◽

Cited By ~ 21

Author(s):

Wei-Cheng Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Molecular Mechanisms ◽

Gender Disparity ◽

B Virus

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Blood-Based Biomarkers in Hepatitis B Virus-Related Hepatocellular Carcinoma, Including the Viral Genome and Glycosylated Proteins

International Journal of Molecular Sciences ◽

10.3390/ijms222011051 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11051

Author(s):

Sanae Hayashi ◽

Katsuya Nagaoka ◽

Yasuhito Tanaka

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Early Detection ◽

Molecular Mechanisms ◽

Hbv Infection ◽

Public Health Issue ◽

B Virus ◽

Disease Specific ◽

Glycosylated Proteins

Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) development and is a global public health issue. High performance biomarkers can aid the early detection of HCC development in HBV-infected individuals. In addition, advances in the understanding of the pathogenesis of HBV infection and in clinical laboratory techniques have enabled the establishment of disease-specific tests, prediction of the progression of liver diseases, including HCC, and auxiliary diagnosis of HCC, using blood-based methods instead of biopsies of liver or HCC tissues. Viral factors such as the HBV genotype, HBV genetic mutations, HBV DNA, and HBV-related antigens, as well as host factors, such as tumor-associated proteins and post-translational modifications, especially glycosylated proteins, can be blood-based, disease-specific biomarkers for HCC development in HBV-infected patients. In this review, we describe the clinical applications of viral biomarkers, including the HBV genome and glycosylated proteins, for patients at a risk of HBV-related HCC, based on their molecular mechanisms. In addition, we introduce promising biomarker candidates for practical use, including colony stimulating factor 1 receptor (CSF1R), extracellular vesicles, and cell-free, circulating tumor DNA. The clinical use of such surrogate markers may lead to a better understanding of the risk of disease progression and early detection of HCC in HBV-infected patients, thereby improving their prognosis.

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Additional N-glycosylation mutation in the major hydrophilic region of hepatitis B virus S gene is a risk indicator for hepatocellular carcinoma occurrence in patients with coexistence of HBsAg/anti-HBs

Oncotarget ◽

10.18632/oncotarget.18682 ◽

2017 ◽

Vol 8 (37) ◽

pp. 61719-61730 ◽

Cited By ~ 8

Author(s):

Yan Qiao ◽

Shanshan Lu ◽

Zhihui Xu ◽

Xiaodong Li ◽

Kai Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Risk Indicator ◽

Major Hydrophilic Region ◽

S Gene ◽

B Virus ◽

Hydrophilic Region

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Hepatic Cancer in Chinese: A Chapter in "Geographic Pathology"

The American Journal of Chinese Medicine ◽

10.1142/s0192415x80000025 ◽

1980 ◽

Vol 08 (01n02) ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Klaus F. Wellman ◽

Narasimha R. Vemula ◽

Kurt E. Gerstmann

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chinese Americans ◽

Cross Reactivity ◽

Incidence Rates ◽

Dietary Factors ◽

Chinese Patients ◽

Hepatic Cancer ◽

B Virus

Chinese patients display an unsually high incidience of hepatocellular carcinoma, as expressed in autopsy statistics, in hepatic biopsy specimens, in terms of ratios per 100,000 population, and with regard to standarized mortality rates. As in other ethnic groups, Chinese hepatoma patients show a pronounced numerical preponderance of male over female persons. Whether this sex difference is due to the existnece of cross-reactivity between HBsAg and a male-associated antigen remains to be confirmed. Of the Chinese patients residing abroad, those that were born in China (Idai) are at considerably higher risk of developing hepatic cancer than those born in their countries of residence (Erdai). This observation, per se, strongly argues in favor of an environmental, rather than racial, factor in the causation of such tumors. Among environmental factors suspected of contributing towards the observed inter-ethnic differences in hepatoma incidence rates, parasitic infestations appear to play no role in hepatocarcinogenesis, with the possible exception of clonorchiasis which has been implicated in cholangiocellular carcinomas. Dietary factors, hepatotoxins and alcoholism at beast are of only secondary etiological significance. Cirrhosis has been considered the most important etiological factor in the development of hepatocellular neoplasms. In Chinese patients the proportion of hepatomas arising in cirrhotic livers in many times higher than in Caucasian persons. Surveys have shown that the hepatitis-associated antigen has a high incidence of occurrence in persons of Chinese ancestry, especially those that were born in China, as well as in patients with hepatomas. It has been established that Chinese-Americans are at a very high risk for both hepatitis B virus infection and liver cell carcinoma. In addition, it has been hypothesized that in some families children will be infected with the virus by their mothers during the perinatal period, and that in some cases the infected person swill proceed through several stages (carrier state with retentions of antigen; development of chronic hepatitis; elaboration of cirrhosisis) to the development of hepatocellular carcinoma. It appears, then, that infection with the hepatitis B virus, during the earlier phases of life, is the single most important event in the eventual elaboration of hepatocellular carcinoma. The available epidemioligcal data on Chinese patients constitute a significant body of evidence in support of these conclusions.

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Hepatitis B virus compartmentalization and single-cell differentiation in hepatocellular carcinoma

Life Science Alliance ◽

10.26508/lsa.202101036 ◽

2021 ◽

Vol 4 (9) ◽

pp. e202101036

Author(s):

Frank Jühling ◽

Antonio Saviano ◽

Clara Ponsolles ◽

Laura Heydmann ◽

Emilie Crouchet ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Differentiation ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Single Cell ◽

Host Cell ◽

Molecular Mechanisms ◽

Host Responses ◽

Chronic Hepatitis B Virus ◽

B Virus

Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) world-wide. The molecular mechanisms of viral hepatocarcinogenesis are still partially understood. Here, we applied two complementary single-cell RNA-sequencing protocols to investigate HBV–HCC host cell interactions at the single cell level of patient-derived HCC. Computational analyses revealed a marked HCC heterogeneity with a robust and significant correlation between HBV reads and cancer cell differentiation. Viral reads significantly correlated with the expression of HBV-dependency factors such as HLF in different tumor compartments. Analyses of virus-induced host responses identified previously undiscovered pathways mediating viral carcinogenesis, such as E2F- and MYC targets as well as adipogenesis. Mapping of fused HBV–host cell transcripts allowed the characterization of integration sites in individual cancer cells. Collectively, single-cell RNA-Seq unravels heterogeneity and compartmentalization of both, virus and cancer identifying new candidate pathways for viral hepatocarcinogenesis. The perturbation of pro-carcinogenic gene expression even at low HBV levels highlights the need of HBV cure to eliminate HCC risk.

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