Purdue University Research Group Links HBV Infection with Poor Liver Cancer Prognosis

In an article published in the Journal of Hepatology, Ourania M. Andrisani, PhD, from Purdue University, and colleagues elucidate a link between hepatitis B virus infection and liver cancer.

According to the study, in comparison to other types of cancer, liver cancer has the fastest growing mortality rate in the United States. One major contributing factor to liver cancer progression is infection with the hepatitis B virus (HBV). Although an HBV vaccine exists, it has not been successful in eradicating HBV infection. According to the researchers on the study, the World Health Organization (WHO) estimates that over 250 million people are living with a chronic HBV infection.

In the present time, HBV treatments consist of nucleoside analogs which limit viral replication but do not eliminate viral DNA from the host liver cell or stop the virus from producing viral oncoproteins. In addition, according to the study, in those with late stage liver cancer, the drug sorafenib has been shown to increase survival as well as delay the cancer from spreading. However, it has been shown that certain liver cancer cells that display features of liver cancer stem cells are resistant to the effects of sorafenib. As a consequence, there is a need for new treatment options for this particular subset of liver cancer cells in order to inhibit the formation of these hepatic cancer stem cells.

Hepatic cancer stem cells express certain cell-surface markers such as epithelial cell adhesion molecule (EpCAM), which is the focus of the article. Normally, EpCAM is expressed in liver precursor cells and has been shown to be re-expressed in cells chronically infected with HBV. Therefore, the researchers sought to understand the significance of EpCAM reexpression and determine its relationship to poor prognosis in liver cancer patients.

To accomplish this goal, the researchers utilized qRT-PCR, immunofluorescence microscopy, fluorescence activated cell-sorting (FACS), as well as immunoblotting and other molecular biology techniques. The researchers were able to demonstrate that EpCAM, which is re-expressed in hepatic cancer stem cells, undergoes cleavage, or proteolysis, into a smaller protein domain which travels to the nucleus and activates the Wnt signaling pathway. The Wnt signaling pathway is then responsible for converting liver cells into more stem-like cells. The researchers also showed that these liver cells display CD44 and CD133, which are established markers of hepatic cancer stem cells. This work was done in both in vitro cell-culture lines as well as a transgenic mouse liver cancer model.

In addition, the researchers evaluated existing transcriptomic datasets of liver cancer patients to determine if any connection exists between EpCAM-related genes and liver cancer prognosis. They demonstrated that patients possessing upregulation of stem-like gene signatures, such as EpCAM, had a significantly stronger correlation with poor prognosis.

One of the major conclusions from the study is the potential for new therapeutics to treat liver cancer. In the article, the researchers utilize a gamma-secretase inhibitor in vitro to successfully prevent the cleavage of EpCAM. The researchers envision using this inhibitor in a clinical setting to treat HBV-mediated liver cancer. Furthermore, Professor Andrisani and colleagues, discuss the possibility of using a Wnt signaling inhibitor for treating liver cancer facilitated by HBV infection. In addition to a possible treatment option, the researchers suggest using the stem-like gene signatures implicated in the study to screen liver cancer patients and determine which patients will need these particular therapies.

Samar Mahmoud graduated from Drew University in 2011 with a BA in Biochemistry and Molecular Biology. After two years of working in industry as a Quality Control Technician for a blood bank, she went back to school and graduated from Montclair State University in 2016 with an MS in Pharmaceutical Biochemistry. She is currently pursuing her PhD in Molecular and Cellular Biology at the University of Massachusetts at Amherst.