Identifying the link between chronic hepatitis B infection and liver cancer may one day help cancer patients sidestep the poison of chemotherapy, a Purdue University study suggests.
The research group of Ourania M. Andrisani (oo-RAHN-ee-ah an-dri-SAH-nee) has shown that a protein the hepatitis virus instructs chronically infected liver cells to produce – known as the X protein – under certain conditions instructs precancerous infected liver cells to die. The discovery of how the X protein influences liver cell behavior could be harnessed as an anticancer therapy, turning the X protein's presence in the liver to patients' advantage.
"Instead of chemotherapy, drugs that influence the X protein's behavior might become an alternative cancer therapy," said Andrisani, a professor of basic medical sciences in Purdue's School of Veterinary Medicine. "Rather than give a patient chemicals that damage every cell in the body, therapy based on the X protein could potentially target only cancerous cells, slowing their growth."
The research, which Andrisani conducted with first author Wen Horng Wang, and Gérald Gregori and Ronald L. Hullinger, all of Purdue, appears in the current issue of Molecular and Cellular Biology.
Viruses like the hepatitis B virus incorporate their genes into a healthy cell's genetic material. This way, many viruses not only instruct the cell to make proteins necessary to assemble more virus particles, but they also change or deregulate the normal production of proteins by the healthy cell. One of the genes hepatitis B introduces into liver cells is called the X gene, a short sequence of DNA that "expresses," or creates, the X protein – a building block essential for creating hepatitis B. Scientists have suspected the gene and its corresponding protein to be accomplices in cancer development as well.
"The X protein is present in the livers of all chronic hepatitis B patients, and several past studies have implicated it in liver cancer development," Andrisani said. "We decided to look at the effect of the X protein on liver cells in isolation to find out what it was doing to the cells' life cycle."
As a molecular biologist, Andrisani studies how cells receive chemical messages from the body that instruct them to grow, differentiate and die at proper times – actions that are necessary for health in highly specialized bodies like our own. Andrisani's team theorized that the X protein was the chemical messenger that caused the liver cells to behave erratically, putting them out of step with healthy liver tissue.
"To find out what instructions the X protein was feeding the cells, we worked with samples of mouse liver tissue in the lab," she said. "We first took the X gene from hepatitis B and inserted it into liver cell nuclei. Then, after the gene started producing the X protein in the cells, we watched the behavior of these mouse liver samples to see whether they conformed to healthy liver cell life cycles."
To ease observation, they used samples that were only a single layer of cells thick. Observing these modified cells, the team found that the effects of the X gene were a bit complicated.
"The gene does different things to cells at different stages of their lives," Andrisani said. "We found, for example, that liver cells in the beginning of their life cycle will grow vigorously when the X protein is around, but under conditions of stress, it encourages them to die. We have other data, as yet unpublished, that shows the X protein can essentially 'rescue' cells from dying at the appropriate time. Of course, if you see cells growing uncontrollably and refusing to die, then you are looking at the mechanisms of cancer development."