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DNA Repair Mechanisms In The Pathogenesis Of Hepatocellular Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$339,078.00
Summary
Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection, alcoholism and liver iron accumulation. Despite the vast amount of in ....Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection, alcoholism and liver iron accumulation. Despite the vast amount of information available regarding these risk factors, the way in which they alter normal liver cells to make them cancerous remains undefined. The majority of liver cancers, regardless of cause, develop in severely scarred, or cirrhotic liver in the presence of chronic liver inflammation. Such an environment causes liver cells, which are usually stable and not dividing, to continue replicating in response to injury; such continued cell division can lead to damaged genetic information in the DNA of these cells. Many cancers are associated with chromosomal damage, including broken ends and deleted genetic material. The main focus of this project to investigate how defective repair of disrupted genetic information contained in DNA of chromosomes in damaged liver cells contributes to the development of liver cancer. Using mice lacking specific genetic information to repair DNA double strand breaks, we plan to investigate whether abnormalities in DNA repair mechanisms in liver cells damaged by diethylnitrosamine (DEN) predisposes liver cells to regenerate abnormally thereby progressing to cancer. We have clues that 7 specific sites in chromosomes where loss of key genes may promote HCC formation. These studies will greatly enhance our understanding of the molecular basis by which HCC develops. The ultimate goal of this research is to develop effective screening and treatment strategies to prevent or interrupt the process of liver cancer development in at-risk individuals.Read moreRead less
Clonal Proliferation Of Hepatocytes And Progression Of Liver Disease In Chronic Hepatitis B Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$420,558.00
Summary
Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver c ....Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver cell population occur because of the immune response against infected hepatocytes. We hypothesize that the immune response kills infected hepatocytes and provides and growth advantage to hepatocytes that can no longer be infected with HBV. This leads to the clonal proliferation of HBV-negative hepatocytes that over time become the major cell population in the liver. We will study human liver tissue using molecular techniques to detect the HBV DNA that integrates randomly into cell DNA during HBV infection. We will then determine the copy number of specific integrated virus-cell junctions as a measure of hepatocyte proliferation. Sections of fixed liver will also be examined for changes in histology and frequency of HBV infection. These studies will determine if foci of HBV-negative hepatocytes are clonal. This finding would suggest that a major role of the immune system in the development of liver cancer is to restrict the genetic pool of hepatocytes. We hypothesise that liver cancer beings with a very specific survival advantage for hepatocytes that lack HBV replication and antigen expression, and that proliferation of these cells expands the pool of potentially altered HCC precursor cells.Read moreRead less