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Liver cancer is one of the most common cancers worldwide. While the exact molecular mechanisms that are associated with the development of liver cancer are not entirely understood, potential causes include exposure to environmental toxins and drugs, alcohol consumption, and chronic infections of the liver with viruses such as the hepatitis B virus (HBV). The work in my laboratory focuses on studying processes involved in hepatocyte transformation; hepatocytes are the major epithelial cell of the liver.

Our main interest is to understand the causes of HBV-associated liver cancer. Approximately 80% of liver cancers can be attributed to chronic infections with HBV. Precisely how HBV causes liver cancer is unknown but is thought to involve the consequences of immune-mediated destruction of HBV-infected hepatocytes, and resultant liver regeneration, as well as activities of HBV proteins such as the HBV X protein (HBx). HBx is a multifunctional protein that regulates HBV replication and influences cellular transcription, proliferation, apoptotic and signal transduction pathways. However, the exact means by which HBx influences such diverse processes is not understood. We demonstrated that one HBx activity is modulation of cellular cytosolic calcium levels, which results in the activation of Pyk2 and Src kinases and regulation of apoptotic and cell proliferation pathways. Alterations in calcium signaling have numerous consequences for cellular metabolism and may explain many of the diverse functions that have been attributed to HBx and its putative role in the development of HBV-associated liver cancer. We recently demonstrated that HBx modulation of calcium signaling is through regulation of the mitochondrial permeability transition pore (MPTP). We are continuing to study HBx-induced calcium signaling as well as other activities associated with HBx expression to determine the precise mechanism through which this protein influences such a diverse array of cellular pathways. These studies are performed in established human liver cell lines, in cultured primary rat hepatocytes, and in vivo through the use of adenovirus recombinants that can transduce HBV into the livers of mice. Such studies should help delineate how this protein and chronic HBV infections can lead to transformation of liver cells and the development of liver cancer.

We are also exploring how alcohol exposure and HBV infections can synergize to enhance the development of liver cancer. There is evidence that chronic HBV infections combined with chronic alcohol consumption dramatically increase progression to the development of liver cancer, but precisely how this occurs is unknown. We are using a model system of cultured primary rat hepatocytes that are infected with HBV and exposed to alcohol to define cellular signaling pathways that are impacted by the combination of these stimuli and evaluating the consequence for hepatocyte physiology.

Our third area of interest is the development of alternative liver models that can be used to study the consequence of viral infections and/or drug, toxin, or alcohol exposure for liver physiology. In collaboration with Dr. Moses Noh, an engineer at Drexel University, we are using recent advances in microfabrication and microfluidic technologies to develop a miniaturized human liver model system. This system uses small numbers of primary liver cells that are maintained in layered co-cultures in microfabricated microchannels. This type of system facilitates the long-term maintenance of liver cells, mimics the microenvironment of the liver, and can be used to study various aspects of liver physiology. We have successfully generated layered co-cultures of primary rat hepatocytes and liver sinusoid endothelial cells and are now expanding to studies with primary human liver cells. An advantage of this novel liver model system is that it requires very small numbers of cells while still generating a system that simulates a basic functional unit of the liver. Our long-term goal is to use this system to study the response of human liver cells to various stimuli such as an HBV infection and/or alcohol and drug exposure.

 
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