As the most common type of liver cancer, hepatocellular carcinoma (HCC) has become the third leading cause of cancer-related deaths worldwide, and HCC cases are increasing in the United States and worldwide. While chemotherapy, surgery, and liver transplants can help some patients, targeted therapies for HCC could save millions of lives.
Recent research has provided clues about a potential target -- circadian clock proteins inside cells that help coordinate changes in body function throughout the day. But most of these studies have only hinted at an indirect link between circadian clock function and HCC, such as the observed disruption of circadian rhythms in cells collected from liver cancer patients.
"Earlier studies didn't give us a real grasp of how to target a process within liver cancer cells using a specific therapy. In this paper, we took the first step in that direction." Dr. Steve A. Kay, the corresponding author of the paper and professor of neurology at the Keck School of Medicine of USC, said.
Co-author Heinz-Josef Lenz, Ph.D., associate director of clinical research at the USC Norris Comprehensive Cancer Center, said, "We are very excited to have identified an innovative treatment strategy that may ultimately improve outcomes for patients with liver cancer. By targeting the circadian clock, we target not only the tumor cells but also the area around the tumor, which could help improve the efficacy of other targeted therapies."
In order to elucidate the role of clock proteins in HCC, Kay, Lenz, and their colleagues performed a series of experiments using a combination of cell culture, genomic analysis, and animal models.
First, they found that two key biological clock proteins, CLOCK and BMAL1, are essential for the replication of liver cancer cells in cell culture. When CLOCK and BMAL1 are inhibited, the replication process of liver cancer cells is disrupted -- ultimately leading to apoptosis. Triggering apoptosis and then self-destruction is the goal of many modern cancer treatments.
Next, they used their toolbox of genomic samples to learn more about the roles of CLOCK and BMAL1, based on years of research on clock proteins in vivo. They found that removing the two clock proteins decreased levels of the enzyme Wee1 and increased levels of the enzyme's inhibitor, P21.
Finally, they tested their findings in vivo. Mice injected with human liver cancer cells that had not been genetically modified developed larger tumors, but mice injected with human liver cancer cells genetically modified to inhibit CLOCK and BMAL1 had almost no tumor growth.
Understanding how cancer cells hijack clock proteins is a big step toward stopping the spread of liver cancer, but the authors have many more questions to answer. For example, Kay and his team wanted to explore the relationship between the clock protein, Wee1, and the P53 gene. The P53 gene helps prevent the growth of tumors in the body, and mutations in the P53 gene have long been associated with an increased risk of a variety of cancers.
Kay and his team also hope to begin testing experimental drugs that target CLOCK and BMAL1 in patients with liver cancer. The work is part of a larger study analyzing clock proteins in several types of cancer, including glioblastoma, leukemia and colorectal cancer.