Obesity, alcoholism, and chronic hepatitis all increase the risk of getting liver cancer, which is the third leading cause of cancer death worldwide. Obesity in particular is driving a significant increase in liver cancer in the United States. These three health problems also increase cellular stress in the liver, but until now it has not been clear if there is a direct biological link between cellular stress and the development of liver cancer.
In a new study, University of Iowa researchers have identified an unexpected molecular link between liver cancer, cellular stress, and these health problems that increase the risk of developing this cancer.
The study, published Dec. 19 in the journal PLOS Genetics, shows that a protein called CHOP, which had previously been thought to generally protect against cancer, actually promotes liver cancer in mice and may do the same in humans.
"Obesity, alcoholism, and viral hepatitis are all known independently to cause cellular stress and to induce expression of CHOP," says Thomas Rutkowski, Ph.D., assistant professor of anatomy and cell biology in the UI Carver Colleges of Medicine and senior study author. "So this finding suggests a biological pathway that links those ‘upstream’ health problems to liver cancer at the end."
CHOP is a transcription factor that is produced when cells experience certain kinds of stress. It is known to promote cell death, or apoptosis. Usually, factors that promote cell death protect against cancer by causing damaged cells to die.
The study shows that, despite its role in cell death, CHOP actually is elevated in liver tumor cells in mice. Furthermore, mice without CHOP are partially protected from liver cancer, developing fewer and smaller tumors than the normal mice in response to liver cancer-causing drugs. The mice without CHOP also had less liver scarring and inflammation than mice with the protein.
Tissue samples from human patients show that CHOP also is elevated in human liver tumors compared to surrounding non-tumor tissue from the same patients.
"We turned out to be completely wrong about CHOP. We found that it contributes to the development of liver cancer in mice and is associated with liver cancer in humans," Rutkowski says. "CHOP is indeed killing cells, just as we thought it would, but we think the consequence of this killing is not the prevention of tumors, but instead the stimulation of inflammatory signals in the liver that cause excessive proliferation of other cells,” he explains.
Rutkowski notes that although this proposed mechanism is not proven yet, it is consistent with what is known about the role of CHOP.
Collaboration was critical to the success of the study, Rutkowski adds. Postdoctoral researcher Diane McCabe in his lab performed most of the experiments, and McCabe and Rutkowski worked closely with cancer biology expert Adam Dupuy, Ph.D., UI associate professor of anatomy and cell biology, and his graduate student Jesse Riordan. Another collaboration with Michael Icardi, M.D., UI associate professor of pathology, gave Rutkowski access to liver tissue samples from patients that allowed the team to show the association between elevated CHOP and human liver cancer.
Having implicated CHOP as a contributing factor in liver cancers associated with obesity, alcoholism, and hepatitis, Rutkowski next wants to learn whether CHOP acts early in the process of tumor formation or if it plays a role in helping established tumors to grow. He also is interested in identifying the other proteins that partner with CHOP to promote liver cancer.
"This discovery opens up an avenue into a new pathway that promotes liver cancer," he says. "Once we know what those other genes are that interact with CHOP, then maybe we can find a ‘druggable’ target molecule. The hope is that down the line scientists will be able to convert that finding into something therapeutically useful for patients.
"Federal funding is the backbone of this kind of research, which has the potential to make unexpected discoveries that, in this case, could help improve cancer treatment," he adds.
The work was funded by grants from the National Institute of Diabetes, Digestive, and Kidney Disorders of the National Institutes of Health. (DK084058)