Transcriptional Activation By Hbv
The genome of hepadnaviruses has a similar organization to that of retroviruses and areas of significant sequence homology have been identified . This observation, together with the fact that replication of both groups of virus involves reverse transcriptase, suggests that retroviruses and hepadnaviruses have common ancestral origins. The X ORF, encoding the HBx protein, is located at the 3 end of the linearized pregenomic RNA in a position analagous to the location of sequences that encode accessory transcriptional regulating proteins of complex retroviruses . This prompted investigation of a role for HBx in transcriptional regulation, a role subsequently confirmed. HBx is the smallest HBV protein and is required for WHV infection and presumably for the replication of HBV in vivo. The X ORF is conserved in mammalian hepadnaviruses associated with HCC. Oncogenic effects of avian hepadnaviruses, which are devoid of the X ORF, have not been demonstrated. It is unclear whether trans-activation is the essential HBx function required for HBV replication in vivo. Evidence that it is comes from the observation that HBx is required to activate transcription of the core gene in vivo in transgenic mice . Activation of the expression of cellular growth regulatory genes during processes that are potentialy oncogenic has been an area of major interest in evaluating the trans-activator function of HBx.
Mechanisms of transcriptional activation by HBx
Factors Associated With Hbv
Thanks to the advances in the molecular biology of HBV, the pathogenesis of HBV-related HCC is largely clarified . The pathogenesis of HCC in patients with CHB can be divided according to HBV-related direct and indirect mechanisms. Direct oncogenic effects of HBV include HBV-host genome integration and HBV-encoded oncogenic protein. The integration of HBV DNA into the host genome induces both host chromosomal instability and insertional mutagenesis of HCC-related genes. This integration in the host genome most frequently happens in the telomerase reverse transcriptase region and myeloid/lymphoid or mixed-lineage leukemia 4 gene. Dysregulation of telomerase and histone methyltransferase expression subsequently increase the risk of hepatocarcinogenesis. Truncated HBV pre-S/S mutation induces surface protein synthesis imbalance and may increase endoplasmic reticulum stress and decrease tumor suppressor gene expression, and thus, it may play a primary role in oncogenesis. Among HBV-encoded proteins, HBV X protein has the most oncogenic effect in hepatocarcinogenesis. HBV X protein is a multifunctional regulator, and it is involved in several cancer-related molecular mechanisms, including alteration of signal pathways , DNA repair , apoptosis , mitochondrial function , and expression of noncoding RNA . Through these mechanisms, HBV X protein directly contributes to HCC development.
Liver Cancer And Hepatitis B
People with hepatitis B have an increased risk of liver cancer. Unlike hepatitis C, people with hep B are at risk for liver cancer even if they do not have cirrhosis. While the overall incidence of cancer has stabilized or decreased in the United States, the rate of liver cancer is increasing, making it the second deadliest cancer.
There are two categories of liver cancerprimary and secondary. Primary refers to cancer that starts in the liver. The most common primary liver cancer in adults is hepatocellular carcinoma , sometimes called hepatoma. Hepatitis B causes 60 to 80 percent of primary liver cancer cases worldwide.
Secondary or metastatic cancer, occurs when cancer starts in another part of the body and spreads to the liver. Colorectal cancer is known for this, with roughly half of all cases metastasizing to the liver. There are other types of benign and malignant tumors of the liver.
Risk Factors The majority of HCC occurs in people with risk factors. The more risk factors, the greater the chances are for developing liver cancer. Chronic hepatitis B infection is a risk factor. Anything that leads to cirrhosis is a liver cancer risk. Cirrhosis is linked to more than 80 percent of all HCC. Other risk factors for HCC are:
Signs and Symptoms
One of the reasons that liver cancer is particularly life-threatening is because signs and symptoms often do not appear until it is in its later stages. Symptoms of liver cancer include:
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Hbv And Extracellular Vesicles
Extracellular vesicles , as carriers and transporters, can directly transfer proteins, lipids, and nucleic acids between various cells in the microenvironment and play an important role in regulating the progression of malignant tumors. The level of miRNAs with negative immunologic modulation roles in EVs secreted by HBV-infected liver cells was increased. These EVs can be taken up by innate immune cells, inhibiting cellular function, and helping the virus resist the host immune response.138,139
Hepatocellular Carcinoma And Hepatitis Virus
- Received 24 April 2002.
Hepatitis B And Your Cancer Risk
Along with hepatitis C, hepatitis B is a leading cause of liver cancerin the US. Take these important steps to reduce your liver cancer risk.
Along with hepatitis C, which also attacks the liver, hepatitis B is a leading cause of liver cancer in the United States. So knowing your risk, getting vaccinated and getting screened are important steps to reduce your risk for liver cancer.
Chronic hepatitis B can wreak havoc on your liver, but you probably wont know its happening.
Hepatitis B is a viral infection that attacks the liver. Usually in the first six months, adults may have mild symptoms that are easily ignored or no symptoms at all. Children typically do not have symptoms, either. If your body does not clear the virus, it becomes a chronic infection that can stay in the body for decades, causing damage with no symptoms at all.
When patients find out they have chronic hepatitis B, they are often surprised, says Jessica Hwang, M.D., associate professor in Internal Medicine. Because its so quiet, stealthy and lingering, it can cause damage and the patient might not know about it until very, very late.
Who is at risk for hepatitis B?
Hepatitis B is spread through contact with infected blood and body fluids. You cannot get hepatitis B through casual contact like kissing, hugging or sharing eating utensils. It cannot be spread through coughing or sneezing.
You are at increased risk for hepatitis B infection if you:
How to prevent hepatitis B
If you have hepatitis B
If I Have No Symptoms How Would I Know If I Have Hepatitis B
To confirm whether or not you have hepatitis B, you will need blood tests.
If you have at least one risk factor , you should ask your health care provider to be tested for hepatitis B. Also, you should be tested for hepatitis B if:
- you were born in a region where hepatitis B is more common, including Asia, Africa, southern and eastern Europe, the Pacific Islands, the Middle East, and the Arctic
- one or both of your parents immigrated from a region where hepatitis B is more common
- you live or travel to regions where hepatitis B is more common
- you have a family history of liver disease or liver cancer
- you have been in prison
- you are pregnant
- you have ever used injection drugs, even just once
- you have unexplained abnormal liver enzymes or if
- you receive medicines that suppress the immune system.
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Dr Samuel So On Liver Cancer & Hepatitis B And C
Samuel So, MD, is the Lui Hac Minh Professor and Professor of Surgery at the Stanford University School of Medicine, founder of the Stanford Liver Cancer Center, and the founder and executive director of the Asian Liver Center at Stanford University School of Medicine.
Q: You are recognized internationally for your expertise in Hepatitis B, Hepatitis C, and liver cancer prevention, research, treatment, and policy. What led you to this field of medicine?
It has been an interesting journey. I started my career as a transplant surgeon. In those relatively early days in the field of transplantation, I devoted my time and efforts to optimize the short-term and long-term outcomes of pediatric and adult transplant recipients. In the process, I became very interested in studying the causes of and prevention of life-threatening viral infections in immunocompromised transplant recipients.
Q: Based on your experience, can you provide any insights on the current landscape of liver cancer both in the U.S. and globally and its link with Hepatitis B and C?
Q: Your current clinical specialty focuses on a âmultidisciplinary approach in the treatment of primary liver cancer and management of chronic Hepatitis B infection.â Hepatitis B impacts as many as 2.2 million people in the U.S. and can lead to liver cancer if untreated â however, more than half of people with the virus are unaware they have it. Why is there such a lack of awareness in the U.S. around Hepatitis B?
What Causes Liver Cancer
Many factors play a role in the development of cancer. Because the liver filters blood from all parts of the body, cancer cells from elsewhere can lodge in the liver and start to grow. Cancers that begin in the gastrointestinal tract often spread to the liver. Liver cells can regenerate after injury . Sometimes the regeneration of liver cells is associated with changes that have been linked to the development of liver cancers.
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Prevention Of Hepatitis B Virus
1Department of Gastroenterology, Renai branch, Taipei City Hospital
Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine ,
5Hepatitis Research Center, and Department of Medical Research, National Taiwan University, National Taiwan University Hospital , Taipei 10002, Taiwan .
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© The Author 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License , which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Hepatitis B Virus Integration Sites
Given the landscape described above, the status of HBV DNA in Peruvian HCC is hardly compatible with paradigmatic liver carcinogenic mechanisms, such as insertional mutagenesis and continuous pro-oncogenic activity of HBx. A hit-and-run activity, a non-cell autonomous/micro-environmental process, or some host predisposition are possible alternative explanations for liver tumorigenesis in Peruvian patients. Nevertheless, we assessed HBV DNA integration sites into genome of tumor cells using HBV-Alu PCR method. In total, nine integration sites were cloned from seven HBsAg patients and two OBI patients . Each integration site was different, with most of them located in gene introns. Regarding the genes altered, no common pathway was readily discernible.
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Hepatitis And Liver Cancer
Institute of Medicine Committee on the Prevention and Control of Viral Hepatitis Infection Editors: Heather M. Colvin and Abigail E. Mitchell.
The global epidemic of hepatitis B and C is a serious public health problem. Hepatitis B and C are the major causes of chronic liver disease and liver cancer in the world. In the next 10 years, 150,000 people in the United States will die from liver disease or liver cancer associated with chronic hepatitis B virus or hepatitis C virus infections. Today, between 800,000 and 1.4 million people in the United States have chronic hepatitis B and between 2.7 and 3.9 million have chronic hepatitis C. People most at risk for hepatitis B and C often are the least likely to have access to medical services. Reducing the rates of illness and death associated with these diseases will require greater awareness and knowledge among health care workers, improved identification of at-risk people, and improved access to medical care.
Hepatitis B is a vaccine-preventable disease. Although federal public health officials recommend that all newborns, children, and at-risk adults receive the vaccine, about 46,000 new acute cases of the HBV infection emerge each year, including 1,000 in infants who acquire the infection during birth from their HBV-positive mothers. Unfortunately, there is no vaccine for hepatitis C, which is transmitted by direct exposure to infectious blood.
What Are The Symptoms
What happens to you when you contract hepatitis B depends largely on the age at which you first become infected and how well your immune system copes with the virus. If you are infected as an adult, you may have a brief illness with mild or moderate symptoms such as jaundice, dark urine, fatigue, abdominal discomfort, and loss of appetite. As an adult, you have a 95% chance of clearing the infection completely and developing lifelong protection against this virus. The acute infection rarely leads to severe illness that requires a liver transplant.
Most babies and children exposed to this virus never have signs and symptoms. Unfortunately, they are more likely to become carriers of hepatitis B for life because their immune system is unable to fight and clear the virus from their body. In these cases, chronic infections are often not detected or picked up until much later in life when the person becomes seriously ill with liver disease.
Chronic hepatitis B infection goes through different phases that also show how well your body is coping with the virus. Although most people with chronic hepatitis B have an inactive disease and will remain healthy, about one in four will have active disease that may lead to cirrhosis , liver failure, and liver cancer.
People who are healthy with an inactive disease may still be at risk of virus reactivation, especially when their immune system is weakened by medicines such as chemotherapy or by other viral infections.
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The Link Between Hepatitis And Liver Cancer
In medical terms, liver cancer is also known as hepatocellular carcinoma. The liver cells called hepatocytes make up 80 percent of your liver.
Scarring of your liver is usually caused by cirrhosis, which is recognized as the main risk factor for liver cancer. Cirrhosis can be caused by hepatitis B, hepatitis C, and viral hepatitis, alcohol abuse, autoimmune diseases, hemochromatosis, and other diseases that lead to chronic inflammation of the liver. Chronic hepatitis B or C infections may also lead to liver cancer.
Hbv Hepatocyte Apoptosis And Hcc
Hepatocytes are particularly susceptible to Fas Ligand induced apoptosis . FasL is a member of the tumour necrosis factor superfamily playing well-defined roles in the regulation of the immune system, embryonic development and tissue homeostasis. During acute HBV infection, liver-infiltrating lymphocytes will expose hepatocytes to FasL and induce widespread cell death . While mature hepatocytes are highly sensitive to FasL, they are resistant to other death ligands such as TNF or TRAIL . However, upon HBV infection, hepatocytes also become susceptible to these death ligands . This sensitisation to death stimuli may be an important contributor to the extensive liver destruction that can follow hepatitis B infection. It has been shown that replicating HBV causes hepatocyte apoptosis . Interestingly, reports using transgenic mice containing the whole HBV genome have shown that enhanced hepatocarcinogenesis is associated with increased apoptosis and compensatory regeneration .
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Hepatitis B Virus Dna Prevalence
We conducted a molecular survey on viruses present in HCC and NTL matched pairs of 65 Peruvian patients, for whom we had both DNA and RNA at disposal. The clinical demography of the patients studied are displayed in Table . We used both nested- and quantitative PCR methods to detect and quantify HBV, HCV, as well as hepatitis D virus in HCC/NTL of the 65 patients. Two patients were infected with HCV subtype 1b, whereas a single patient was infected with HDV genotype 3. These three patients were HBV carriers as well.
Table 1 Baseline demographical and clinical features of the Peruvian HCC patients.Figure 1
Viral status modulates clinico-biological features of Peruvian patients with HCC. Box-and-whiskers plots. Age of patients with HCC according to the HBV markers detected. AFP serum levels measured according to the HBV markers detected. For age and AFP comparisons, P values were provided by Kruskal-Wallis test for global comparisons of the three groups while they were obtained by Mann-Whitney U test for the comparisons of groups against each other. Bar charts. ns, not significant. Tumor nodularity according to the HBV markers detected. Level of mutations affecting TERT-encoding gene according to the HBV markers detected. Error bars represent the standard deviation. P values were provided by Chi-square test.
Hbv Associated Hcc Wnt/fzd/
The Wnt cascade has emerged as a critical regulator of stem cells and activation of Wnt signalling has been associated with numerous cancers . Wnt signalling is activated by the binding of one of the 19 mammalian extracellular soluble secreted Wnt ligands to single or multiple members of 10 mammalian Frizzled receptors . Binding of Wnt to FZD can lead to activation of the canonical -catenin pathway or the non-canonical c-Jun N-terminal kinase and Ca++ pathways , however, here we limit our discussion to the canonical -catenin pathway as its role is best characterised in context of liver and liver cancer.
Wnt/-catenin signal transduction pathway. Wnt binding to the FZD/LRP5/6 receptor complex leads to inhibition of GSK3 enzyme activity and the -catenin destruction complex, which allows newly synthesized -catenin to accumulate and translocate to the nucleus , where it binds with co-factors to form a transcriptionally active complex. Wnt signalling can be inhibited at the cell surface by various naturally occurring pathway inhibitors such as sFRPs and DKK, which bind to Wnt and LRP5/6 respectively.
PI3K/AKT and Ras/ERK1/2 pathways
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