Hepatocellular carcinoma cells hijack biological clock proteins to proliferate and spread

As the most common type of liver cancer, hepatocellular carcinoma (HCC) has become the third leading cause of cancer-related deaths worldwide, and cases of HCC are on the rise in the United States and around the world.

Recent studies have provided clues about a potential target—the intracellular circadian clock proteins that help orchestrate changes in body function throughout the day. The reported disturbance of circadian rhythms in cells extracted from individuals with liver cancer, for example, has only hinted at an indirect relationship between biological clock function and HCC.

Researchers from the University of Southern California, the University of California, Riverside, the University of Pittsburgh, and China's Fourth Hospital of Zhejiang University School of Medicine have not only directly linked the biological clock protein to liver cancer, but have also demonstrated how cancer cells hijack the biological clock mechanism to divide and spread. They also discovered that blocking essential biological clock proteins might halt cancer cell growth. The results of the study were published online on January 3, 2023 in PNAS under the title "Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle".

Dr. Steve A. Kay, the corresponding author of the paper and professor of neurology at the University of Southern California's Keck School of Medicine, commented, "Previous research did not provide a clear picture of how to target mechanisms within liver cancer cells with a specific treatment strategy. This paper is a starting step in that approach."

To elucidate the role of biological clock proteins in HCC, Kay, Lenz and their colleagues conducted a series of experiments using a combination of cell culture, genomic analysis, and animal models.

First, they discovered that two crucial biological clock proteins, CLOCK, and BMAL1, are required for hepatocellular carcinoma cell reproduction in cell culture. When CLOCK and BMAL1 are suppressed, hepatocellular carcinoma cells' replication is impaired, eventually leading to apoptosis. Many modern cancer therapies aim to induce apoptosis and eventually self-destruction.

Following that, they utilized their toolbox of genomic samples to further understand the role of CLOCK and BMAL1 based on years of research on biological clock proteins in vivo. They discovered that removing these two biological clock proteins reduced the amounts of the enzyme Wee1 while increasing the levels of P21, an inhibitor of this enzyme.

Kay says, "That's exactly what we want, because when it comes to cancer cell proliferation, P21 is a brake and Wee1 is a gas pedal."

Finally, they tested their findings in vivo. Mice injected with human liver cancer cells that had not been genetically modified grew larger tumors, but mice injected with human liver cancer cells that had been genetically modified to suppress CLOCK and BMAL1 showed little to no tumor growth.

Understanding how cancer cells hijack the biological clock protein is a big step toward stopping the spread of liver cancer, but these authors have more questions to answer. For example, Kay and his team hope to explore the relationship between the biological clock protein, Wee1, and the P53 gene, which helps prevent tumor growth in the body, and mutations in the P53 gene have long been associated with an increased risk of many types of cancer.

"We really need to understand this correlation," Kay said, "to better decide which patients would benefit the most from CLOCK and BMAL1 targeted therapy."

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